No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Effect of Peritumoral Infiltration of Local Anesthetic Before Surgery on Survival in Early Breast Cancer
Abstract
Purpose:
Preventing metastases by using perioperative interventions has not been adequately explored. Local anesthesia blocks voltage-gated sodium channels and thereby prevents activation of prometastatic pathways. We conducted an open-label, multicenter randomized trial to test the impact of presurgical, peritumoral infiltration of local anesthesia on disease-free survival (DFS).
Methods:
Women with early breast cancer planned for upfront surgery without prior neoadjuvant treatment were randomly assigned to receive peritumoral injection of 0.5% lidocaine, 7-10 minutes before surgery (local anesthetics [LA] arm) or surgery without lidocaine (no LA arm). Random assignment was stratified by menopausal status, tumor size, and center. Participants received standard postoperative adjuvant treatment. Primary and secondary end points were DFS and overall survival (OS), respectively.
Results:
Excluding eligibility violations, 1,583 of 1,600 randomly assigned patients were included in this analysis (LA, 796; no LA, 804). At a median follow-up of 68 months, there were 255 DFS events (LA, 109; no LA, 146) and 189 deaths (LA, 79; no LA, 110). In LA and no LA arms, 5-year DFS rates were 86.6% and 82.6% (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95; P = .017) and 5-year OS rates were 90.1% and 86.4%, respectively (HR, 0.71; 95% CI, 0.53 to 0.94; P = .019). The impact of LA was similar in subgroups defined by menopausal status, tumor size, nodal metastases, and hormone receptor and human epidermal growth factor receptor 2 status. Using competing risk analyses, in LA and no LA arms, 5-year cumulative incidence rates of locoregional recurrence were 3.4% and 4.5% (HR, 0.68; 95% CI, 0.41 to 1.11), and distant recurrence rates were 8.5% and 11.6%, respectively (HR, 0.73; 95% CI, 0.53 to 0.99). There were no adverse events because of lidocaine injection.
Conclusion:
Peritumoral injection of lidocaine before breast cancer surgery significantly increases DFS and OS. Altering events at the time of surgery can prevent metastases in early breast cancer (CTRI/2014/11/005228).
... Here, breast cancer patients received a pre-operative peritumoral infiltration with lidocaine. 139 Patients in the intervention group had improved survival rates when compared to the control group, which received no intervention. 139 However, the generalisability of these findings remains uncertain, as this large trial, conducted in India, included a population probably different from other countries, with, for instance, limited access to adjuvant treatments like HER2-targeted drugs, routinely used in Europe and North America. ...
... 139 Patients in the intervention group had improved survival rates when compared to the control group, which received no intervention. 139 However, the generalisability of these findings remains uncertain, as this large trial, conducted in India, included a population probably different from other countries, with, for instance, limited access to adjuvant treatments like HER2-targeted drugs, routinely used in Europe and North America. 139 In addition, the study was not double-blinded, and there was no placebo infiltration in the control group. ...
... 139 However, the generalisability of these findings remains uncertain, as this large trial, conducted in India, included a population probably different from other countries, with, for instance, limited access to adjuvant treatments like HER2-targeted drugs, routinely used in Europe and North America. 139 In addition, the study was not double-blinded, and there was no placebo infiltration in the control group. ...
The management of peri-operative pain is one of the pillars of anaesthesia and is of particular importance in patients undergoing surgery for solid malignant tumours. Amongst several options, the most commonly employed analgesic regimens involve opioids, NSAIDs and regional anaesthesia techniques with different local anaesthetics. In recent years, several research reports have tried to establish a connection between peri-operative anaesthesia care and outcome after cancer surgery. Experimental studies have indicated that certain pain management substances may influence cancer progression, mainly by modifying the tumour's response to surgical stress and peri-operative inflammation. However, these promising in-vitro and in-vivo data have yet to be confirmed by randomised clinical trials. The reason for this might lie with the nature of tumour biology itself, and in the diversity of patient and tumour phenotypes. In a translational approach, future research should therefore concentrate on patient and tumour-related factors or biomarkers, which might either influence the tumour and its microenvironment or predict potential responses to interventions, including the choice of the analgesic. This might not only be relevant for the daily practice of clinical anaesthesia, but would also be of great importance for patients undergoing cancer surgery, who might be able to receive an individualised anaesthetic regimen based on their phenotypic profile.
... Most experiments have been carried out on breast cancer where there is significant mechanistic evidence for LAs in suppressing the progression of cancer and improving disease recurrence following surgery (Matos et al. 2022). Most recently, this evidence has received major support from the outcome of a 7-year clinical trial on breast cancer patients (Badwe et al. 2023). Thus, use of perioperative / tumoural lidocaine was found to produce significant survival benefit to patients (Badwe et al. 2023). ...
... Most recently, this evidence has received major support from the outcome of a 7-year clinical trial on breast cancer patients (Badwe et al. 2023). Thus, use of perioperative / tumoural lidocaine was found to produce significant survival benefit to patients (Badwe et al. 2023). At the centre of this phenomenon is functional expression of voltagegated sodium channels (VGSCs) in primary tumours (Soto et al. 2020). ...
... Conversely, as shown here, blocking VGSC activity with lidocaine also reduce the channel protein expression, thereby enhancing its functional effectiveness. Such a property of the VGSC, and its inhibition by lidocaine, would make it more expedient in the context of preventing 'showering' of cancer cells during surgical intervention (Badwe et al. 2023). ...
There is increasing evidence, mostly from breast cancer, that use of local anaesthetics during surgery can inhibit disease recurrence by suppressing the motility of the cancer cells dependent on inherent voltage-gated sodium channels (VGSCs). Here, the possibility that lidocaine could affect cellular behaviours associated with metastasis was tested using the Dunning cell model of rat prostate cancer. Mostly, the strongly metastatic (VGSC-expressing) Mat-LyLu cells were used under both normoxic and hypoxic conditions. The weakly metastatic AT-2 cells served for comparison in some experiments. Lidocaine (1–500 μM) had no effect on cell viability or growth but suppressed Matrigel invasion dose dependently in both normoxia and hypoxia. Used as a control, tetrodotoxin produced similar effects. Exposure to hypoxia increased Nav1.7 mRNA expression but VGSCα protein level in plasma membrane was reduced. Lidocaine under both normoxia and hypoxia had no effect on Nav1.7 mRNA expression. VGSCα protein expression was suppressed by lidocaine under normoxia but no effect was seen in hypoxia. It is concluded that lidocaine can suppress prostate cancer invasiveness without effecting cellular growth or viability. Extended to the clinic, the results would suggest that use of lidocaine, and possibly other local anaesthetics, during surgery can suppress any tendency for post-operative progression of prostate cancer.
... A recent large prospective clinical study by Badwe et al. investigated the impact on survival of preoperative, peritumoral infiltration of lidocaine in patients with early breast cancer [62,63]. Early disease was defined as operable cancer with clinically negative or limited nodal disease and no evidence of distant metastasis. ...
... Moreover, the benefit was present regardless of whether the patients underwent mastectomy or removal of only the tumor and surrounding tissue. Interestingly, no adverse events accompanied lidocaine injection [62]. Limitations of the study include the single-nation nature, the lack of placebo control, and the fact that investigators were unblinded to the study's intervention. ...
... Limitations of the study include the single-nation nature, the lack of placebo control, and the fact that investigators were unblinded to the study's intervention. Despite the limitations, these results are remarkable, given the lack of toxicity, the ease and low cost of intervention, and the large sample size of the trial [62]. ...
Preclinical evidence suggests that voltage gradients can act as a kind of top-down master regulator during embryogenesis and orchestrate downstream molecular-genetic pathways during organ regeneration or repair. Moreover, electrical stimulation shifts response to injury toward regeneration instead of healing or scarring. Cancer and embryogenesis not only share common phenotypical features but also commonly upregulated molecular pathways. Voltage-gated ion channel activity is directly or indirectly linked to the pathogenesis of cancer hallmarks, while experimental and clinical studies suggest that their modulation, e.g., by anesthetic agents, may exert antitumor effects. A large recent clinical trial served as a proof-of-principle for the benefit of preoperative use of topical sodium channel blockade as a potential anticancer strategy against early human breast cancers. Regardless of whether ion channel aberrations are primary or secondary cancer drivers, understanding the functional consequences of these events may guide us toward the development of novel therapeutic approaches.
... Oncological outcomes are summarized in Table 2. Among all included studies, only one study reported positive results (infiltration of lidocaine around the tumor) [20]. ...
... The quality of the included studies is illustrated in Fig 2. One study did not report the method of random sequence generation [20]. Blinding to anesthetists is challenging to implement during the perioperative period. ...
... Earlier studies on lidocaine infusion were predominantly designed to investigate pain management in patients with breast cancer rather than oncological outcomes [40,41]. Herein, only one study administered lidocaine as an intervention to evaluate its anti-tumorigenic effect [20], revealing that peritumoral injection of 0.5% lidocaine significantly prolonged disease-free survival and overall survival rate in patients with early breast cancer; this was the only study reporting positive clinical outcomes in the studies included in this review. This result confirms that intravenous infusion is not the sole method of lidocaine administration. ...
Objective
Anesthesia is correlated with the prognosis of cancer surgery. However, evidence from prospective studies focusing on breast cancer is currently limited. This systematic review aimed to investigate the effect of anesthesia-related interventions on oncological outcomes following breast cancer surgery in prospective studies.
Methods
Literature searches were performed from inception to June. 2023 in the Pubmed, Web of Science, Embase, and ClinicalTrials databases. The main inclusion criteria comprised a minimum of one-year follow-up duration, with oncological outcomes as endpoints. Anesthesia-related interventions encompassed, but were not limited to, type of anesthesia, anesthetics, and analgesics. The risk of bias was assessed using the Cochrane Risk of Bias Tool.
Results
A total of 9 studies were included. Anesthesia-related interventions included paravertebral nerve block (3), pectoral nerve block (1), sevoflurane (2), ketorolac (2), and infiltration of lidocaine (1). Cancer recurrence, metastasis, disease-free survival, or (and) overall survival were assessed. Among all included studies, only infiltration of lidocaine was found to prolong disease-free survival and overall survival.
Conclusion
Regional anesthesia and propofol did not improve oncological outcomes following breast cancer surgery. The anti-tumorigenic effect of ketorolac warrants future studies with larger sample sizes. Perioperative infiltration of lidocaine around the tumor may be a promising anti-tumorigenic intervention that can prolong overall survival in patients with early breast cancer.
... Importantly, the metastasis-promoting function of Na v 1.5 can be inhibited in preclinical models using VGSC blockers, including phenytoin and ranolazine, suggesting that Na v 1.5 may represent a novel anti-metastatic target for therapeutic intervention [17,18]. Furthermore, peri-operative administration of the VGSC blocker lidocaine has recently been shown to significantly improve disease-free survival in women with early breast cancer [19]. ...
... In addition, VGSCinhibiting drugs have been shown to decrease tumour growth and metastasis in murine breast cancer models [17,18]. Furthermore, a recent clinical trial has shown that presurgical peritumoral treatment with lidocaine significantly improves disease-free and overall survival in women with early breast cancer [19]. In conclusion, our results reveal a positive feedback mechanism by which Na + influx through Na v 1.5 promotes glycolytic H + production to increase invasive capacity and drive breast cancer metastasis. ...
Solid tumours have abnormally high intracellular [Na⁺]. The activity of various Na⁺ channels may underlie this Na⁺ accumulation. Voltage-gated Na⁺ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na⁺/K⁺ ATPase, thus promoting H⁺ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na⁺ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na⁺ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.
... The discrepancy between laboratory conditions and the much more complex "real-life" tumor biology, including the TME, might explain the current mismatch [139]. First, evidence that LAs might influence the TME has been provided by a recent study assessing the effects of a preoperative peritumoral infiltration with lidocaine vs. no intervention in breast cancer patients, whereby a significantly prolonged survival rate was observed in the lidocaine group [140]. However, as there were several limitations to this particular study, including the lack of a placebo control, the results should be interpreted with caution [140]. ...
... First, evidence that LAs might influence the TME has been provided by a recent study assessing the effects of a preoperative peritumoral infiltration with lidocaine vs. no intervention in breast cancer patients, whereby a significantly prolonged survival rate was observed in the lidocaine group [140]. However, as there were several limitations to this particular study, including the lack of a placebo control, the results should be interpreted with caution [140]. ...
Surgical excision of the primary tumor represents the most frequent and curative procedure for solid malignancies. Compelling evidence suggests that, despite its beneficial effects, surgery may impair immunosurveillance by triggering an immunosuppressive inflammatory stress response and favor recurrence by stimulating minimal residual disease. In addition, many factors interfere with the immune effectors before and after cancer procedures, such as malnutrition, anemia, or subsequent transfusion. Thus, the perioperative period plays a key role in determining oncological outcomes and represents a short phase to circumvent anesthetic and surgical deleterious factors by supporting the immune system through the use of synergistic pharmacological and non-pharmacological approaches. In line with this, accumulating studies indicate that anesthetic agents could drive both protumor or antitumor signaling pathways during or after cancer surgery. While preclinical investigations focusing on anesthetics’ impact on the behavior of cancer cells are quite convincing, limited clinical trials studying the consequences on survival and recurrences remain inconclusive. Herein, we highlight the main factors occurring during the perioperative period of cancer surgery and their potential impact on immunomodulation and cancer progression. We also discuss patient management prior to and during surgery, taking into consideration the latest advances in the literature.
... Characterisation of luminal and triple-negative breast cancer with HER2 Low protein expression (Atallah et al.) [14]. [15][16][17] Effect of Peritumoral Infiltration of Local Anaesthetic Before Surgery on Survival in Early Breast Cancer (Badwe et al.) [15]. This is a surprising trial using the recently explored concept that local anesthesia seems to block voltage-gated sodium channels, present in cancer cells, hindering the activation of pro-metastatic pathways. ...
... Characterisation of luminal and triple-negative breast cancer with HER2 Low protein expression (Atallah et al.) [14]. [15][16][17] Effect of Peritumoral Infiltration of Local Anaesthetic Before Surgery on Survival in Early Breast Cancer (Badwe et al.) [15]. This is a surprising trial using the recently explored concept that local anesthesia seems to block voltage-gated sodium channels, present in cancer cells, hindering the activation of pro-metastatic pathways. ...
This narrative work highlights a selection of published work from 2023 with potential implications for breast cancer practice. We feature publications that have provided new knowledge immediately relevant to patient care or for future research. We also highlight guidelines that have reported evidence-based or consensus recommendations to support practice and evaluation in breast cancer diagnosis and treatment. The scope of selected highlights represents various domains and disciplines in cancer control, from prevention to treatment of early and advanced breast cancer.
... Over time, LAs have been found to exert a range of alternative effects, including modulation of the inflammatory cascade, inhibition of inflammatory mediators, antiarrhythmic [55], protection against thromboembolism [56], antimicrobial activity, and even anticancer properties [57][58][59][60][61][62]. ...
... The strategy of drug repurposing offers a promising avenue for these agents, given their minimal side effects, negligible drug interactions, affordability, and global availability. The remarkable beneficial effects of LAs are increasingly being investigated in relation to additional comorbidities, such as cancer, as evidenced by Badwe et al. and other referenced studies [60]. While their safety and efficacy are well established, there is an urgent need for increased research into the expansive therapeutic applications of local anesthetics. ...
The use of low-dose local anesthetics (LAs) has significantly transformed patient care by providing rapid and effective relief of pain and other clinical conditions while minimizing recovery time. This study aims to identify and describe the existing scientific evidence on the therapeutic use of low-dose LAs in various conditions and to identify gaps in the current literature in order to prioritize future research. This systematic scoping review adhered to the methodological guidelines outlined in the Arksey and O’Malley framework, which includes five distinct stages. Of the 129 studies included, 37.98% (n = 49) were clinical trials, 55.03% (n = 71) were observational studies, and 6.97% (n = 9) were systematic reviews. The most commonly reported indication for the use of low-dose LAs was chronic pain management (72.86%), followed by acute pain management (13.17%). Additionally, non-pain-related indications were also identified (13.95%). Overall, the administration of low-dose, short-acting LAs demonstrated favorable outcomes in terms of pain management and reduction in anxiety and depression scales, thereby having a positive impact on the patients’ quality of life. This review represents the first systematic scoping review regarding the therapeutic role of LAs. To substantiate the reported positive effects on efficacy and safety, further rigorous research comprising larger, well-designed randomized controlled trials (RCTs) and long-term outcome monitoring is imperative.
... In a xenograft mouse model of TNBC, phenytoin reduced tumor growth and metastasis to the lung, liver, and spleen [45]. Treatment with lidocaine, which blocks sodium channels and is commonly used as an anesthetic, has been shown to improve the survival of mice with peritoneal metastases from MDA-MB-231 TNBC cells [46], and peritumoral injection of lidocaine before breast cancer surgery significantly increases disease-free and overall survival in human patients [47]. There is currently an active Phase I clinical trial (NCT04048278) evaluating the effect of intravenous lidocaine on the biology of circulating tumor cells in pancreatic cancer. ...
Cellular plasticity and the ability to avoid terminal differentiation are hallmarks of cancer. Here, we review the evidence that tumor cells themselves can take on properties of neurons of the central nervous system, which can regulate tumor growth and metastasis. We discuss recent evidence that axon guidance molecules and regulators of electrical activity and synaptic transmission, such as ion channels and neurotransmitters, can drive the oncogenic and invasive properties of tumor cells from a range of cancers. We also review how FDA-approved treatments for neurological disorders are being tested in pre-clinical models and clinical trials for repurposing as anti-cancer agents, offering the potential for new therapies for cancer patients that can be accessed more quickly.
... [23] Such operation can eliminate the risk of tumor cell metastasis and shorten the delivery distance of photothermal agents when compared to the systemic administration. [24][25][26] Attributed to these advantageous attributes, peritumoral injection has been explored as an efficient yet low-risk administration for superficial tumor PTT. ...
Peritumoral subcutaneous injection has been highly envisioned as an efficient yet low‐risk administration of photothermal agents for superficial tumor photothermal therapy. However, obstructed by complex subcutaneous tissue, the delivery of injected photothermal agents to the specific tumor remains a critical issue. Herein, the study reports a polydopamine (PDA)‐encapsulated spherical core/shell nanomotor with fluorescent indocyanine green (ICG) immobilized on its PDA shell. Upon the first near‐infrared (NIR‐I) irradiation, this motor can generate favorable photothermal heat, and meantime, emit a robust ICG fluorescence in the second near‐infrared window (NIR‐II). The heat turns the motor into an active photothermal agent able to perform thermophoretic propulsion along the irradiation direction in subcutaneous tissue, while the ICG fluorescence can direct the subcutaneous propulsion of motors toward specific tumor through real‐time NIR‐II imaging. These functions endow the motor with the ability of moving to tumor after being injected at peritumoral site, enabling an enhanced photothermal therapy (PTT). The results demonstrated herein suggest an integrated nanorobotic tool for the superficial PTT using peritumoral administration, highlighting an NIR‐II imaging‐directed subcutaneous propulsion.
... Compared to general anesthesia, epidural anesthesia did not improve the overall survival of patients with GC after surgery, but patients undergoing epidural combined with general anesthesia had fewer postoperative complications and lower rates of metastatic recurrence [30,31]. As for local anesthesia, a multicenter randomized controlled trial showed that local infiltration with lidocaine improved overall survival and reduced metastasis in breast cancer patients [32]. Examining general anesthesia, a retrospective study that included 2,856 postoperative patients with GC found that patients in the propofol-based intravenous anesthesia group had better survival outcomes than those in the sevoflurane-based inhalational anesthesia group [8]. ...
Background
Different anesthetic drugs and techniques may affect survival outcomes for gastric cancer (GC) after surgery. In this study, we investigated the association between sedated and unsedated gastroscopy on survival outcomes in patients with GC after surgery.
Methods
This was a retrospective study of patients who were diagnosed with GC by gastroscopy and underwent gastrectomy from January 2013 to December 2017. They were grouped based on the examination modality: propofol-based sedated gastroscopy or unsedated gastroscopy. Propensity score matching (PSM) was used to balance the baseline variables. Survival outcomes and distant metastases were compared between these two groups.
Results
Finally, 673 patients were enrolled, 160 in the sedated gastroscopy group and 513 in the unsedated gastroscopy group. After PSM, there were 160 patients in each group. There was no significant difference in overall survival outcomes in the sedated gastroscopy group compared to the unsedated gastroscopy group before PSM (HR = 0.761, 95% CI: 0.531–1.091, P = 0.139) or after PSM (HR = 0.874, 95% CI: 0.564–1.355, P = 0.547). There was no significant difference in the incidence of distant metastases between the two groups before PSM (16.9% vs. 20.7%, P = 0.294) or after PSM (16.9% vs. 23.8%, P = 0.126). To confirm that our patients behaved similarly to other studies, we performed a multivariate analysis and the results showed that sex, pathological TNM stage, Borrmann type, adjuvant treatment, and surgical resection range were all independent factors affecting survival outcomes in our patients.
Conclusion
Our results showed no significant difference in the effects of sedated gastroscopy vs. unsedated gastroscopy on survival outcomes or distant metastases of patients after gastrectomy for GC.
... These data have been supported by some retrospective studies but not confirmed by others [45]. Recently, the results of a randomized study by Badwe suggested that the peritumoral infiltration of lidocaine at the time of surgery leads to statistically significant and clinically meaningful improvements in OS (overall survival) and DFS (disease-free survival) in patients with early-stage breast cancer [49]. ...
Background:
Hypnosis sedation has recently been used for anesthesia in breast oncologic surgery.
Methods:
Between January 2017 and October 2019, 284 patients from our Breast Clinic (Cliniques Universitaires Saint-Luc, Université Catholique de Louvain) and from the Jolimont Hospital were prospectively included in an interventional non-randomized study approved by our two local ethics committees and registered on clinicaltrials.gov (NCT03330117). Ninety-three consecutive patients underwent surgery while on general anesthesia (GA group). Ninety-two consecutive patients underwent surgery while on general anesthesia preceded by a hypnorelaxation session (GAVRH group). Ninety-five consecutive patients underwent surgery while exclusively on hypnosis sedation (HYPS group). Clinical parameters (pain score, anxiety and distress score) were measured on days 0, 1 and 8 for all patients. All evaluable patients underwent NLR (neutrophil-to-lymphocyte ratio) and CRP (C-reactive protein) dosage on days 0, 1 and 8.
Results:
Pain scores and anxiety scores were statistically lower in the HYPS group on days 1 and 8, as was the duration of NSAID consumption. NLR and CRP values were significantly inferior on day 1 for all patients who benefited from hypnosis sedation.
Conclusions:
Some benefits of hypnosis sedation (reduction in postoperative pain, decrease in NSAID consumption) are correlated with a significant reduction in inflammatory parameters in the perioperative process.
... p = 0.017) and OS (HR 0.71, 95% CI 0.53-0.94, p = 0.019) [193]. ...
Cancer recurrence and metastasis remain critical challenges following surgical resection, influenced by complex perioperative mechanisms. This review explores how surgical stress triggers systemic changes, such as neuroendocrine responses, immune suppression, and inflammation, which promote the dissemination of residual cancer cells and circulating tumor cells. Key mechanisms, such as epithelial–mesenchymal transition and angiogenesis, further enhance metastasis, while hypoxia-inducible factors and inflammatory responses create a microenvironment conducive to tumor progression. Anesthetic agents and techniques modulate these mechanisms in distinct ways. Inhaled anesthetics, such as sevoflurane, may suppress immune function by increasing catecholamines and cytokines, thereby promoting cancer progression. In contrast, propofol-based total intravenous anesthesia mitigates stress responses and preserves natural killer cell activity, supporting immune function. Opioids suppress immune surveillance and promote angiogenesis through the activation of the mu-opioid receptor. Opioid-sparing strategies using NSAIDs show potential in preserving immune function and reducing recurrence risk. Regional anesthesia offers benefits by reducing systemic stress and immune suppression, though the clinical outcomes remain inconsistent. Additionally, dexmedetomidine and ketamine exhibit dual effects, both enhancing and inhibiting tumor progression depending on the dosage and context. This review emphasizes the importance of individualized anesthetic strategies to optimize long-term cancer outcomes. While retrospective studies suggest potential benefits of propofol-based total intravenous anesthesia and regional anesthesia, further large-scale trials are essential to establish the definitive role of anesthetic management in cancer recurrence and survival.
... For instance, an analysis involving 1600 participants found that peritumoral injection of lidocaine before breast cancer surgery significantly decreased distant recurrence rates. [6] Another study indicated that the use of lidocaine during cancer surgery was associated with improved overall survival. [7] Additionally, lidocaine was shown to enhance the effectiveness of conventional anticancer treatments. ...
Background
Over the past 2 decades, lidocaine’s application in oncologic surgery has received significant attention. It has potential antitumor effects and acts as a chemosensitizer. The aim of this study is to analyze the process and frontiers of lidocaine application in oncologic surgery over the past 20 years.
Methods
A bibliometric analysis was performed and CiteSpace software was used to conduct metrology, co-occurrence, and cluster analysis. Articles retrieved from the Web of Science database from January 1, 2004 to May 27, 2024. Inclusion criteria comprised peer-reviewed original articles or reviews on lidocaine and cancer, excluding conference abstracts, corrigenda, repeated publications, and unrelated articles.
Results
A total of 956 articles were included in this study. Two hundred seventeen were selected for detailed analysis. The annual publication count showed an overall increasing trend, peaking in 2022. The United States emerged as the leading country in terms of publication frequency and centrality. Major research themes included lidocaine’s antiproliferative effects, enhancement of chemotherapy efficacy, and various administration methods.
Conclusion
Based on the above results, we draw a conclusion that the relationship between lidocaine and cancer has garnered increasing attention, with research in this area rapidly developing. Lidocaine exhibits significant antitumor effects and potential as a chemosensitizer, enhancing the efficacy of traditional chemotherapy. These findings underscore the importance of further research to fully elucidate lidocaine’s mechanisms and its potential clinical applications in oncology.
... Lidocaine, which activates T2R14, has been demonstrated to be effective in improving overall survival and disease-free survival when injected peritumorally in breast cancer patients undergoing surgical resection. 68 If similar clinical responses are seen in PTC, then bitter therapies like lidocaine may be valuable in the treatment algorithm for aggressive recurrent PTC. In a similar vein, given the feasibility and practicality of injectable bitter agonists, low-risk PTC that border the threshold between active surveillance and surgery (which was not certified by peer review) is the author/funder. ...
Background
Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with a 20% recurrence rate. Bitter taste receptors (T2Rs) and their genes ( TAS2Rs ) may regulate survival in solid tumors. This study examined T2R expression and function in PTC cells.
Methods
Three PTC cell lines (MDA-T32, MDA-T68, MDA-T85) were analyzed for expression using RT-qPCR and immunofluorescence. Live cell imaging measured calcium responses to six bitter agonists. Viability and apoptosis effects were assessed using crystal violet and caspase 3/7 activation assays. Genome analysis of survival was conducted.
Results
TAS2R14 was consistently highly expressed in all cell lines. Five bitter agonists produced significant calcium responses across all cell lines. All bitter agonists significantly decreased viability and induced apoptosis. Higher TAS2R14 expression correlated with better progression-free survival in patients (p<0.05).
Conclusions
T2R activation by bitter agonists induces apoptosis and higher TAS2R expression is associated with survival, suggesting potential therapeutic relevance in thyroid cancer management.
... Generalized nerve blocking drugs also offer a strategy to target multiple neural subtypes within the tumor. Supporting evidence for this approach comes from a prospective clinical trial that administered lidocaine around the tumor immediately prior to surgery and found a small but significant improvement in disease-free and overall survival (104). ...
The tumor microenvironment influences cancer progression and response to treatments, which ultimately impacts the survival of patients with cancer. The sympathetic nervous system (SNS) is a core component of solid tumors that arise in the body. In addition to influencing cancer progression, a role for the SNS in the effectiveness of cancer treatments is beginning to emerge. This review explores evidence that the SNS impairs chemotherapy efficacy. We review findings of studies that evaluated the impact of neural ablation on chemotherapy outcomes and discuss plausible mechanisms for the impact of neural signaling on chemotherapy efficacy. We then discuss implications for clinical practice, including opportunities to block neural signaling to improve response to chemotherapy.
... However, the perioperative period, characterized by the activation of neural and inflammatory signaling pathways, which can disrupt immune function and affect cancer progression, has been associated with increased metastatic potential (11,12). The choice of anesthetics during breast cancer surgery has been demonstrated to influence patient outcomes and the risk of postoperative recurrence (13,14). ...
Breast cancer is the most prevalent cancer among women worldwide, characterized by a high mortality rate and propensity for metastasis. Although surgery is the standard treatment for breast cancer, there is still no effective method to inhibit tumor metastasis and improve the prognosis of patients with breast cancer after surgery. Propofol, one of the most widely used intravenous anesthetics in surgery, has exhibited a positive association with improved survival outcomes in patients with breast cancer post‑surgery. However, the underlying molecular mechanism remains to be elucidated. The present study revealed that triple negative breast cancer cells, MDA‑MB‑231 and 4T1, exposed to propofol exhibited a significant decrease in cell viability. Notably, propofol exhibited minimal cytotoxic effects on HUVECs under the same conditions. Furthermore, propofol significantly inhibited the migration and invasion ability of MDA‑MB‑231 and 4T1 cells. Propofol promoted apoptosis in 4T1 cells through upregulation of Bax and cleaved caspase 3, while downregulating B‑cell lymphoma‑extra large. Concomitantly, propofol induced cell cycle arrest of 4T1 cells by downregulating cyclin E2 and phosphorylated cell division cycle 6. Furthermore, propofol exhibited excellent anticancer efficacy in a 4T1 breast cancer allograft mouse model. The present study sheds light on the potential of propofol as an old medicine with a novel use for breast cancer treatment.
... Additionally, lidocaine has been reported to enhance breast cancer treatment outcomes by reducing the mitochondrial membrane potential in tumor cells, promoting Cyt C release, and inhibiting protein synthesis linked to mitochondria [96]. This finding has been applied in clinical research, with Badwe et al. discovering that peri-tumoral injection of lidocaine before breast cancer surgery significantly increases disease-free survival and overall survival and can prevent tumor metastasis [99]. As our understanding of lidocaine's mechanisms has evolved, its applications have extended well beyond its traditional use as a local anesthetic. ...
Focus on the implications of common perioperative drugs for mitochondrial quality control and their subsequent impact on the overall physiological condition has been increasing. This review discusses the effects of perioperative drugs, such as intravenous and inhaled anesthetics, analgesics, local anesthetics on mitochondrial quality and their underlying mechanisms. These drugs influence mitochondrial properties, including morphology, dynamics, energy metabolism, and protein expression, thereby affecting the clinical outcomes of patients undergoing surgery. Such effects can be either protective or detrimental and are contingent upon multiple variables such as the specific drug used, dosage, application timing, and the patient's overall health status. Recognizing the effects of these perioperative drugs on mitochondrial quality control is crucial to selecting safer anesthetic protocols, reducing postoperative complications, enhancing postoperative recovery, and gaining insights into the development of innovative treatment methodologies and optimization of perioperative care.
... These aforementioned findings are supported by six retrospective clinical trials that observed better outcomes after the use of epidural in colorectal cancer surgery [18][19][20][21][22][23][24][25][26]. Two randomized controlled trials also demonstrated that epidural or local injection of lidocaine improves OS after colon or breast cancer resection [27,37]. The mechanisms by which local anesthetics improve survival are still under debate. ...
Background: Surgical inflammatory pain decreases the innate and adaptive immune antitumor response and favors residual circulating tumor cells. Objectives: This study investigated whether minimally invasive surgeries (laparoscopic and robotic procedures), which are less painful and inflammatory, improved oncological outcomes after colorectal resection compared to laparotomy. Methods: This research was a single-center propensity score-matched study involving patients who underwent colectomy and rectum resection from July 2017 to December 2019. Results: Seventy-four laparotomies and 211 minimally invasive procedures were included. Minimally invasive procedures were associated with less blood loss (0 mL vs. 75 mL, p < 0.001), shorter length of stay (8 days vs. 12 days, p < 0.001), and fewer complications at 3 months (11.8% vs. 29.4%, p = 0.02) compared to laparotomies. No difference in overall survival (OS) and recurrence-free survival (RFS) at 3 years between groups was observed. Univariate Cox regression analyses demonstrated that age and ASA > 3 can negatively impact OS, while adjuvant chemotherapy can positively influence OS. pT3-T4 stage and postoperative pain could negatively influence RFS. Multivariate Cox regression analyses concluded that age (HR 1.08, p < 0.01) and epidural analgesia (HR 0.12, p = 0.03) were predictors for OS. Lidocaine infusion (HR 0.39, p = 0.04) was a positive predictor for RFS. Conclusions: Minimally invasive procedures reduce postoperative complications and shorten the length of hospital stay compared to major surgeries without improving prognosis. However, the administration of local anesthetics through neuraxial anesthesia or intravenous infusion could improve survival and decrease the occurrence of relapses.
... We recently showed that lidocaine, a local anesthetic already approved for use in HNSCC surgeries, activates T2R14 and downstream apoptosis in HNSCC cells [6]. Interestingly, a recent multicenter randomized controlled clinical trial demonstrated that breast cancer patients receiving peritumoral injection of 1% lidocaine prior to surgery had greater disease-free and overall survival compared with uninjected patients [8,9]. As breast cancer cells also express T2R14 [10], this survival benefit may be due to T2R14 activation, further supporting a potential role for T2R agonists as therapies for solid tumors. ...
Head and neck squamous cell carcinomas (HNSCCs) are cancers that arise in the mucosa of the upper aerodigestive tract. The five-year patient survival rate is ~50%. Treatment includes surgery, radiation, and/or chemotherapy and is associated with lasting effects even when successful in irradicating the disease. New molecular targets and therapies must be identified to improve outcomes for HNSCC patients. We recently identified bitter taste receptors (taste family 2 receptors, or T2Rs) as a novel candidate family of receptors that activate apoptosis in HNSCC cells through mitochondrial Ca ²⁺ overload and depolarization. We hypothesized that targeting another component of tumor cell metabolism, namely glycolysis, may increase the efficacy of T2R-directed therapies. GLUT1 ( SLC2A1 ) is a facilitated-diffusion glucose transporter expressed by many cancer cells to fuel their increased rates of glycolysis. GLUT1 is already being investigated as a possible cancer target, but studies in HNSCCs are limited. Examination of immortalized HNSCC cells, patient samples, and The Cancer Genome Atlas revealed high expression of GLUT1 and upregulation in some patient tumor samples. HNSCC cells and tumor tissue express GLUT1 on the plasma membrane and within the cytoplasm (perinuclear, likely co-localized with the Golgi apparatus). We investigated the effects of a recently developed small molecule inhibitor of GLUT1, BAY-876. This compound decreased HNSCC glucose uptake, viability, and metabolism and induced apoptosis. Moreover, BAY-876 had enhanced effects on apoptosis when combined at low concentrations with T2R bitter taste receptor agonists. Notably, BAY-876 also decreased TNFα-induced IL-8 production, indicating an additional mechanism of possible tumor-suppressive effects. Our study demonstrates that targeting GLUT1 via BAY-876 to kill HNSCC cells, particularly in combination with T2R agonists, is a potential novel treatment strategy worth exploring further in future translational studies.
... Furthermore, compared with general anesthetics, a beneficial role of local anesthetics in attenuating tumor growth and metastasis was suggested [12][13][14]. Encouragingly, a recent clinical trial reported that peritumoral injection of lidocaine before breast cancer surgery can significantly increases disease-free survival (DFS) and overall survival (OS) [15]. Local anesthetics may exert antitumor effects on cancer cells through indirect (e.g., preservation of immune functions) [8] and direct pathways (e.g., inhibition of cancer cell proliferation through the mitogen-activated protein kinase (MAPK) pathway) [12,16,17]. ...
Different anesthetics exert different effects on the long-term outcomes of various cancers. The TWIK-related acid sensitive potassium 3 (TASK-3) channel is an important target of anesthetics and is upregulated in various cancers. However, the role and underlying mechanism of TASK-3 channel in the effects of anesthetics on ovarian cancer remain unknown. Here, we tested whether the TASK-3 channel contributes to the effects of anesthetics on ovarian cancers. We found that the TASK-3 channel was overexpressed in human ovarian cancer and ovarian cancer cell lines. Clinically relevant concentrations of lidocaine, as a TASK-3 channel inhibitor, exert inhibitory effects on tumor growth and metastasis of ovarian cancer cells in vitro and in vivo, whereas the TASK-3 channel potent activator sevoflurane had protumor effects and propofol had no significant effects on tumor growth and metastasis of ovarian cancer. Knockdown of the TASK-3 channel by TASK-3 shRNA attenuated the effects of lidocaine and sevoflurane. Moreover, mitochondrial TASK-3 channel contributes to the effects of lidocaine and sevoflurane on the mitochondrial functions of ovarian cancer. Taken together, the TASK-3 channel, especially the mitochondrial TASK-3 (MitoTASK-3) channel, is a molecular substrate for the effects of lidocaine and sevoflurane on the tumor growth and metastasis of ovarian cancer.
... Some studies have shown that regional anesthesia could reduce the risk of metastasis formation. The peritumoral infiltration of lidocaine before surgery at the incision site prevents the formation of metastases, since local anesthetics block the sodium channels [44,45]. ...
Simple Summary
The surgical site infiltration of a local anesthetic, defined as the direct injection of a drug into the surgical field, has proven to be effective in the management of intra- and postoperative pain as it allows one to reduce the use of additional analgesics, such as opioids and non-steroidal anti-inflammatory drugs. Tissue infiltration with local anesthetics is usually performed using a traditional syringe attached to a needle. Innovative devices such as Comfort-in® have been developed, and they do not require a needle. This technology is an injection system that works by infusion via a spring system. It releases the drug at high speed, creating a “fluid needle” that penetrates tissue in less than 1/3 of a second at an average pressure of 3900 pounds per square inch (psi). The depth of penetration depends on the volume of the drug, and the dispersion of the drug is uniform through nebulization. In human medicine, local anesthesia with a needle-free injection system has been used in infiltrations, incisions, dental extractions, urology, diabetology, virology, dermatology, and pediatrics. The needle-free injection system has recently been proposed as a valid alternative method also in veterinary medicine for vaccination and drug administration in swine.
Abstract
The surgical site infiltration of a local anesthetic is defined as the direct injection of a drug. This study aimed to compare the effects of surgical site infiltration with 4 mg kg⁻¹ lidocaine using a Comfort-in device and traditional syringe on oxidative status and intra- and postoperative pain in dogs undergoing regional mastectomy. Sixty adult female dogs divided into C (Comfort-in device), S (traditional syringe), and CTR (control) groups received 2 µg kg⁻¹ dexmedetomidine and 4 mg kg⁻¹ tramadol IM, 5 mg kg⁻¹ tiletamine/zolazepam IV, and isoflurane. The physiological and anesthesiological parameters were measured. The assessment of intra- and postoperative responses to the surgical stimulus was performed using a cumulative pain scale (CPS score of 0–4) and the Colorado Pain Scale (CSU-CAPS score of 0–4). The hematological and biochemical parameters and inflammatory oxidative status were measured. The CPS scores showed no significant differences between the C and S groups (p = 0.236), while the comparison between the CTR, C, and S groups, respectively, showed a significant difference (p < 0.001). The postoperative analgesia scores were significantly lower in the C group compared to those of the S and CTR groups (p < 0.001). In the C group, no subject received rescue analgesia during the intra- and postoperative periods. The level of oxidative inflammatory stress was lower in group C than those in S and CTR groups, and no side effects were observed in all the groups.
... Another class of medications that could influence the nerve-cancer crosstalk is lidocaine, a local anesthetic that alters nerve signal conduction. In breast cancer surgery, the peritumoral injection of 0.5% lidocaine 7-10 min before surgery resulted in a small but significantly increased DFS and OS [74]. ...
Simple Summary
There is an interaction between cancer and neural cells. This interaction was discovered as early as 1948. The first messenger of this interaction, called crosstalk, was discovered shortly after and was named the nerve growth factor (NGF). This factor influences many different organs, among them, the immune system and the nervous system. Its influence on cancer is little-known. We summarized the present knowledge on the interaction between cancer and nerves with a special focus on prostate and pancreas cancer, cancers that are richly innervated and therefore called neurotrophic. We found that this interaction plays a crucial role as a regulator of the cancer microenvironment. The surgical, chemical, and radiotherapeutical ablation of nerves has been shown to have a therapeutic effect on both cancers. There seems to be a potential relationship between cancer and psychosocial biology via neurotransmitters and neurotrophins such as the NGF. The effect of beta-blockers on cancer seems limited so far.
Abstract
Introduction: Crosstalk occurs between nerve and cancer cells. These interactions are important for cancer homeostasis and metabolism. Nerve cells influence the tumor microenvironment (TME) and participate in metastasis through neurogenesis, neural extension, and axonogenesis. We summarized the past and current literature on the interaction between nerves and cancer, with a special focus on pancreatic ductal adenocarcinoma (PDAC), prostate cancer (PCa), and the role of the nerve growth factor (NGF) in cancer. Materials/Methods: We reviewed PubMed and Google Scholar for the relevant literature on the relationship between nerves, neurotrophins, and cancer in general and specifically for both PCa and PDAC. Results: The NGF helped sustain cancer cell proliferation and evade immune defense. It is a neuropeptide involved in neurogenic inflammation through the activation of several cells of the immune system by several proinflammatory cytokines. Both PCa and PDAC employ different strategies to evade immune defense. The prostate is richly innervated by both the sympathetic and parasympathetic nerves, which helps in both growth control and homeostasis. Newly formed autonomic nerve fibers grow into cancer cells and contribute to cancer initiation and progression through the activation of β-adrenergic and muscarinic cholinergic signaling. Surgical or chemical sympathectomy prevents the development of prostate cancer. Beta-blockers have a high therapeutic potential for cancer, although current clinical data have been contradictory. With a better understanding of the beta-receptors, one could identify specific receptors that could have an effect on prostate cancer development or act as therapeutic agents. Conclusion: The bidirectional crosstalk between the nervous system and cancer cells has emerged as a crucial regulator of cancer and its microenvironment. Denervation has been shown to be promising in vitro and in animal models. Additionally, there is a potential relationship between cancer and psychosocial biology through neurotransmitters and neurotrophins.
... 43 Because many cancer types use the lymphatic system for metastasis, the question could be asked whether local anesthetic-induced lymphatic inhibition has clinical benefits. 44 The preponderance of data suggests that the main effects of local anesthetics occur due to direct action on the cancer cells themselves. Briefly, cancer cells express voltage-gated sodium channels that alter intracellular sodium, leading to enhanced glycolytic metabolism, altered immune avoidance, enhanced invasion, and increased metastatic potential. ...
General anesthetics adversely alters the distribution of infused fluid between the plasma compartment and the extravascular space. This maldistribution occurs largely from the effects of anesthetic agents on lymphatic pumping, which can be demonstrated by macroscopic fluid kinetics studies in awake versus anesthetized patients. The magnitude of this effect can be appreciated as follows: a 30% reduction in lymph flow may result in a fivefold increase of fluid-induced volume expansion of the interstitial space relative to plasma volume. Anesthesia-induced lymphatic dysfunction is a key factor why anesthetized patients require greater than expected fluid administration than can be accounted for by blood loss, urine output, and insensible losses. Anesthesia also blunts the transvascular refill response to bleeding, an important compensatory mechanism during hemorrhagic hypovolemia, in part through lymphatic inhibition. Last, this study addresses how catecholamines and hypertonic and hyperoncotic fluids may mobilize interstitial fluid to mitigate anesthesia-induced lymphatic dysfunction.
... However, four large prospective randomised trials have tested the hypothesis that anaesthetic technique might influence oncologic outcome after cancer surgery. The original and largest compared paravertebral block and total intravenous anaesthesia (TIVA) to volatilebased anaesthesia without a regional block in patients scheduled for breast cancer surgery, 25 another compared peritumoral infiltration with lidocaine, also during breast cancer surgery, 26 and two further trials compared propofol-TIVA to volatile-based inhalational anaesthesia in patients having heterogenous cancer surgeries 27 or breast cancer surgery. 28 The latter two randomised controlled trials found no difference in survival between general anaesthesia with propofol or sevoflurane for cancer surgery. ...
BACKGROUND
Colorectal cancer (CRC) is the second most frequent cause of global cancer mortality. Most patients with CRC require surgical tumour resection, with certain stages of CRC (Stage II/III) also requiring postoperative chemotherapy. The timing of postoperative chemotherapy is largely determined by postoperative recovery. Delayed return to intended oncologic therapy (RIOT) by >8 weeks results in worse oncologic outcomes. RIOT is thus an important surrogate marker of outcome for patients with stage II/III CRC. We will test the hypothesis that anaesthetic technique during CRC resection surgery may affect RIOT.
OBJECTIVE
To test the association between anaesthetic and analgesic technique during CRC surgery and RIOT. To document Short-term Secondary outcomes including individual postoperative complications and a composite of all postoperative complications, the Comprehensive Complications Index (CCI) and to measure the time to recurrence (TTR) of cancer at 3 years.
DESIGN
This is a prospective, international, multicentre, observational cohort study.
SETTING
Global healthcare setting, with >140 centres in >30 nations.
PATIENTS
Inclusion criteria: All patients age >18 years, ASA I–III, with CRC stage I–III scheduled for elective CRC surgery (open or minimally invasive).
Exclusion criteria: Uncontrolled renal or liver disease, restrictive (limiting mobility) heart failure or ischemic heart disease (ASA IV–V). Speech, language, or cognitive difficulties precluding signing informed consent to participate and Stage IV CRC.
PRIMARY OUTCOME MEASURES
Short -term: The duration from day of surgery to RIOT among patients expected to receive postoperative chemotherapy. Long-term: incidence of recurrence and time to recurrence (TTR) at 3 years after primary curative surgery
SECONDARY OUTCOMES
Postoperative complications within 30 days of surgery, length of hospital stay, Days at Home at 30 and 90 days (DAH-30, DAH-90) after surgery, and adverse events related to oncological treatment. We will also assess the burden of preoperative modifiable comorbid disease in patients. Exploratory endpoints will assess practice variation (including incidence of RIOT by demographic e.g. gender of patient, type of institution, country).
RESULTS
N/A.
CONCLUSIONS
N/A.
TRIAL REGISTRATION
The Effects of aNesthesia in COloREctal cancer outcome study: ENCORE, ClinicalTrials.gov Identifier: NCT04493905.
... To enhance the cure and survival rates for breast cancer, it is imperative to reduce local recurrence and metastasis following surgery. The interaction between anesthesia techniques, drug selection, and the cellular immune system may be factors that influence tumor recurrence and metastasis [3]. Propofol-based total intravenous anesthesia (TIVA) has demonstrated enhanced recurrence-free survival and overall survival compared to inhalation anesthesia in both animal models and retrospective clinical studies [4,5]. ...
Background
Anesthesia techniques and drug selection may influence tumor recurrence and metastasis. Neutrophil extracellular trapping (NETosis), an immunological process, has been linked to an increased susceptibility to metastasis in individuals with tumors. Furthermore, recurrence may be associated with vascular endothelial growth factor A (VEGF-A), a mediator of angiogenesis. This study investigates the impact of lidocaine (combined with sevoflurane or propofol anesthesia ) during breast cancer surgery inhibits the expression of biomarkers associated with metastasis and recurrence (specifically H3Cit, NE, MPO, MMP-9 and VEGF-A).
Methods
We randomly assigned 120 women undergoing primary or invasive breast tumor resection to receive one of four anesthetics: sevoflurane (S), sevoflurane plus i.v. lidocaine (SL), propofol (P), and propofol plus i.v. lidocaine (PL). Blood samples were collected before induction and 3 h after the operation. Biomarkers associated with NETosis (citrullinated histone H3 [H3Cit], myeloperoxidase [MPO], and neutrophil elastase [NE]) and angiogenesis were quantified using enzyme-linked immunosorbent assays.
Results
Patient and breast tumor characteristics, along with perioperative management, did not differ between study groups. In intra-group comparisons, S and P groups demonstrated a statistically significant increase in post-operative MPO (S group: 10.39[6.89–17.22] vs. 14.31[8.55–20.87] ng ml-1, P = 0.032; P group: 9.45[6.73–17.37] vs. 14.34[9.87–19.75] ng ml-1, P = 0.035)and NE(S group: 182.70[85.66-285.85] vs. 226.20[91.85-391.65] ng ml-1, P = 0.045; P group: 154.22[97.31–325.30] vs. 308.66[132.36-483.57] ng ml-1, P = 0.037) concentrations compared to pre-operative measurements, whereas SL and PL groups did not display a similar increase. H3Cit, MMP-9, and VEGF-A concentrations were not significantly influenced by the anesthesia techniques and drugs.
Conclusions
Regardless of the specific technique employed for general anesthesia, there was no increase in the postoperative serum concentrations of MPO and NE after perioperative lidocaine infusion compared to preoperative serum concentrations. This supports the hypothesis that intravenous lidocaine during cancer surgery aimed at achieving a cure may potentially decrease the likelihood of recurrence. Further interpretation and discussion of clinical implications are warranted, emphasizing the significance of these findings in the context of cancer surgery and recurrence prevention.
Clinical trial registration
ChiCTR2300068563.
... In this scenario, the incorporation of paravertebral block or other techniques like erector spinae plane block or serratus anterior plane block is often considered fancy and time consuming because of the involvement of gadgets like USG machine, requirement of manpower for positioning, etc. and thus are frequently avoided. The incorporation of lignocaine in wound instillation, has shown beneficial effect on disease free survival 6 and thus when used together, along with bupivacaine, through surgical drains (Drain Block) might prove to be a game changer by comprehensively covering all the aspects of postoperative analgesia. ...
The aim of this study is to report six cases of Drain Block for postoperative analgesia after Modified Radical Mastectomy (MRM). The procedure was carried out at Chittaranjan National Cancer Institute, Kolkata, among 6 female patients aged 32-75 years, who were diagnosed with unilateral breast carcinoma and were posted for MRM. Upon completion of MRM, all patients received a 40 ml solution of local anaesthetic drug mixture comprising of 0.5% isobaric bupivacaine (2 mg/kg) and 2% lignocaine (4 mg/kg) along with 2 ml of 50% Magnesium sulphate as an additive. The 40 ml solution was equally divided and instilled through both the surgical drains (pectoral and axillary drains). Thereafter, the drains were then clamped for 20 minutes and later declamped. The postoperative analgesic outcome was measured in terms of pain and mobility. Pain was quantified with VAS, while mobility was assessed using the evaluation of range of motion with the help of bio-physiological method. The documentation was carried out every 4 hours and continued for twenty-four hours postoperatively. No patient required rescue opioids for the first 18 postoperative hours, with 2 patients having no requirements (VAS < 4) for the first 22 postoperative hours. There were no limitations in ipsilateral arm abduction in immediate postoperative hours in any of the patients. Drain block, combining the beneficial effect of lignocaine on disease free survival in oncology patients and its potency to reduce dependence on postoperative opioids requirements, might prove to be a game changer by comprehensively covering all significant aspects of postoperative analgesia after MRM.
... and OS (HR, 0.71 [95% CI, 0.53-0.94]) [44]. While the results from this study are certainly important, the lack of a true placebo group (e.g., saline injection) is a major limitation. ...
Purpose of Review
Cancer is a leading cause of death, accounting for nearly one in six deaths worldwide. Surgery is a critical intervention in cancer care since it provides a chance of cure or can be used to relieve symptoms in patients with advanced malignancies. Anesthesia (general, regional, or local) and analgesia in any of its delivery modes play critical roles in the treatment and palliation of cancers.
Recent Findings
Experimental data demonstrate that surgery itself and anesthetics can promote the growth of micro-metastatic diseases and the seeding of circulating cancer cells, thereby facilitating cancer progression. While this theory originates from in vitro and animal studies, evidence in humans has remained controversial until recently.
Summary
In this report, we summarize current published evidence on the impact of anesthetics and opioids on cancer progression. We focus our discussion on published human studies with special emphasis on randomized controlled trials.
... By following the National Cancer Grid priorities of research evaluating cost effective interventions, overall costs of medical care can be substantially reduced. In the last decade with support from DAE, the clinical trials centre has published at least ten projects that had the potential to save over 100,000 lives annually when implemented globally [4,5,6,7,8]. All the interventions have been cost-effective and have changed the way cancer is treated globally. ...
Background
Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, with a 20% recurrence rate. Bitter taste receptors (T2Rs) and their genes ( TAS2Rs ) may regulate survival in solid tumors. This study examined T2R expression and function in PTC cells.
Methods
Three PTC cell lines (MDA‐T32, MDA‐T68, and MDA‐T85) were analyzed for expression using RT‐qPCR and immunofluorescence. Live cell imaging measured calcium responses to six bitter agonists. Viability and apoptosis effects were assessed using crystal violet and caspase 3/7 activation assays. Genome analysis of survival was conducted.
Results
TAS2R14 was consistently highly expressed in all cell lines. Five bitter agonists produced significant cytoplasmic and mitochondrial calcium responses across all cell lines. All bitter agonists significantly decreased viability and induced apoptosis. Higher TAS2R14 expression correlated with better progression‐free survival in patients ( p < 0.05).
Conclusions
T2R activation by bitter agonists induces apoptosis, and higher TAS2R expression is associated with survival, suggesting potential therapeutic relevance in thyroid cancer management.
Humans can perceive five canonical tastes: salty, sour, umami, sweet, and bitter. These tastes are transmitted through the activation of ion channels and receptors. Bitter taste receptors (Taste Family 2 Receptors; T2Rs) are a sub-family of 25 G-protein coupled receptor (GPCR) isoforms that were first identified in type II taste bud cells. T2Rs are activated by a broad array of bitter agonists, which cause an increase in intracellular calcium (Ca²⁺) and a decrease in cyclic adenosine 3’,5’-monophosphate (cAMP). Interestingly, T2Rs are expressed beyond the oral cavity, where they play diverse non-taste roles in cell physiology and disease. Here, we summarize the literature that explores the role of T2Rs in apoptosis. Activation of T2Rs with bitter agonists induces apoptosis in several cancers, the airway epithelia, smooth muscle, and more. In many of these tissues, T2R activation causes mitochondrial Ca²⁺ overload, a main driver of apoptosis. This response may be a result of T2R cellular localization, nuclear Ca²⁺ mobilization and/or a remnant of the established immunological roles of T2Rs in other cell types. T2R-induced apoptosis could be pharmacologically leveraged to treat diseases of altered cellular proliferation. Future work must explore additional extra-oral T2R-expressing tissues for apoptotic responses, develop methods for in-vivo studies, and discover high affinity bitter agonists for clinical application.
Background
The peri‐operative period may create a biological environment conducive to cancer cell survival and dissemination. Microscopic residual tumours (micrometastases) can be dislodged even with excellent surgical technique. At the same time, the stress response from surgery can temporarily impair immune function and activate inflammatory processes, increasing the risk of tumour proliferation.
Methods
This narrative review investigates how peri‐operative anaesthetic and analgesic interventions may influence cancer recurrence and metastasis by exploring evidence from both experimental and clinical studies. A comprehensive review of the literature was conducted to identify relevant preclinical and clinical studies published.
Results
While surgery remains the best curative option for many cancers, metastasis remains the leading cause of death. Numerous studies have suggested that different anaesthetic drugs and techniques could impact cancer outcomes including volatile anaesthetic agents; total intravenous anaesthesia with propofol; local anaesthetics; regional anaesthesia; and opioids. This review focuses on these five commonly used anaesthetic approaches and evaluates their potential impact on cancer progression.
Discussion
There is a complex interplay between anaesthetic and analgesic techniques and cancer outcomes. Despite promising data from laboratory experimental models, the balance of available clinical trials indicates an equivalent influence of all evaluated anaesthetic techniques on long‐term oncologic outcomes, except, possibly, for peritumoral or intraperitoneal local anaesthetic infiltration.
Efforts to deconvolve the complex interactions of cancer cells with other components of the tumor micro- and macro-environment have exposed a common tendency for cancers to subvert systems physiology and exploit endogenous programs involved in homeostatic control of metabolism, immunity, regeneration, and repair. Many such programs are engaged in the healing response to surgery which, together with other abrupt biochemical changes in the perioperative period, provide an opportunity for the macroevolution of residual disease. This review relates contemporary perspectives of cancer as a systemic disease with the overlapping biology of host responses to surgery and events within the perioperative period. With a particular focus on examples of cancer cell plasticity and changes within the host, we explore how perioperative inflammation and acute metabolic, neuroendocrine, and immune dyshomeostasis might contribute to cancer evolution within this contextually short, yet crucially influential timeframe, and highlight potential therapeutic opportunities within to further optimize surgical cancer care and its long-term oncological outcomes.
Background
In a previous phase II trial, intraperitoneal local anaesthetics shortened the time interval between surgery and adjuvant chemotherapy, an endpoint associated with improved survival in advanced ovarian cancer. Our objective was to test this in a phase III trial.
Methods
A double-blind, phase III parallel superiority trial was conducted at two university hospitals in Sweden, within a public and centralised healthcare system. Women >18 yr with advanced ovarian cancer scheduled for cytoreductive surgery, an ASA physical status of 1–3 with no speech/language issues, were eligible. Participants were randomly assigned using a central computerised system to receive either ropivacaine 0.2% or saline 0.9% (placebo) intraperitoneally during and after surgery. The primary endpoint was time to return to intended oncologic therapy (RIOT), analysed using t-test and linear regression adjusted for centre.
Results
Of the 225 women randomised between August 2020 and December 2023 (ropivacaine n=113; placebo n=112), 175 were included in the modified intention-to-treat analysis (ropivacaine n=86; placebo n=89). Median age: ropivacaine group 64 yr (56–73 yr), placebo group: 66 yr (57–74 yr). The mean RIOT in the ropivacaine group was 26.5 days vs 25.8 days in the placebo group, with a mean difference of 0.7 days (−2.2 to 3.4 days; P=0.65). Per-protocol analysis of 166 women yielded similar results, mean difference of 0.5 days (−2.4 to 3.4 days; P=0.74) days. There were no differences in short-term recovery or postoperative morbidity.
Conclusion
Intraperitoneal local anaesthetic did not shorten the time to RIOT among women undergoing surgery for advanced ovarian cancer in this trial.
Clinical trial registration
ClinicalTrials.gov (NCT04065009), European Union Clinical Trials Register (2019-003299-38/SE).
It is almost 2 decades since it was first hypothesized that anesthesia technique might modulate cancer biology and thus potentially influence patients’ long-term outcomes after cancer surgery. Since then, research efforts have been directed towards elucidating the potential pharmacological and physiological basis for the effects of anesthetic and perioperative interventions on cancer cell biology. In this review, we summarize current laboratory and clinical data. Taken together, preclinical studies suggest some biologic plausibility that cancer cell function could be influenced. However, available clinical evidence suggests a neutral effect. Observational studies examining cancer outcomes after surgery of curative intent for many cancer types under a variety of anesthetic techniques have reported conflicting results, but warranting prospective randomized clinical trials (RCTs). Given the large patient numbers and long follow-up times required for adequate power, relatively few such RCTs have been completed to date. With the sole exception of peritumoral lidocaine infiltration in breast cancer surgery, these RCTs have indicated a neutral effect of anesthetic technique on long-term oncologic outcomes. Therefore, unless there are significant new findings from a few ongoing trials, future investigation of how perioperative agents interact with tumor genes that influence metastatic potential may be justified. In addition, building multidisciplinary collaboration to optimize perioperative care of cancer patients will be important.
HER2-positive breast cancer accounts for 10% to 20% of all breast cancer diagnoses. The mAb trastuzumab is crucial in treating this disease, significantly improving survival outcomes. Despite its inclusion in the World Health Organization’s Model List of Essential Medicines, access to trastuzumab remains limited worldwide. In this issue of the journal, Norris and colleagues report that only 45% of eligible patients with HER2-positive breast cancer in the United Kingdom received trastuzumab between 2012 and 2017. This finding in a high-income country with universal health care is worrisome and points toward even greater barriers to access in developing nations. Some solutions to improve accessibility, which we discuss, include shorter durations of trastuzumab treatment and encouraging the registration and availability of biosimilars. The data presented by Norris and colleagues point toward a disconnect between the academic oncology landscape, focused on expensive drugs with marginal benefits, and everyday practice in which even essential interventions may not be available. Ensuring the accessibility to proven, essential medicines should be as relevant as innovation to improve patient outcomes and create a more sustainable healthcare system.
See related article by Norris et al., p. 1298
Objective
This study investigates Enhanced Recovery After Surgery (ERAS®) protocols’ impact on long-term opioid and sedative use following mastectomy with or without implant-based breast reconstruction (IBBR).
Summary Background Data
ERAS® protocols for patients undergoing mastectomy with or without IBBR are associated with decreased length of stay, increased rate of same-day discharge, decreased postoperative pain, and decreased postoperative opioid requirements. However, less is known about their effect on opioid and sedative use beyond 90 days after surgery.
Methods
A retrospective review of all patients undergoing mastectomy with or without IBBR at a single institution between January 2013 and December 2019. Mastectomy ERAS® protocols were implemented in February 2017, creating two groups: pre-ERAS® and ERAS®. Baseline characteristics and prevalence of chronic opioid and sedative use were compared. Univariable and multivariable logistic regression predicted factors associated with increased odds of chronic opioid and sedative use.
Results
756 patients were evaluated: 405 pre-ERAS® and 351 ERAS®. Post-ERAS®, chronic opioid use decreased in opioid-naïve (40% vs. 30%, P =0.024) and opioid-tolerant patients (58% vs. 37%, P =0.002), with no increase in chronic sedative use. There were decreased odds of chronic opioid use for all ERAS® patients (OR=0.57, 95% CI: 0.42-0.76)), and of IBBR patients, those receiving subcutaneous implants (OR=0.31, 95% CI: 0.20-0.48). There was increased chronic opioid-use odds if undergoing bilateral surgery (OR=1.54, 95% CI: 1.14-2.08), two-stage reconstruction (OR=9.78, 95% CI: 5.94-16.09), and for patients with higher PACU pain scores (OR=1.09, 95% CI: 1.03-1.14) or >150 discharge OMEs (OR=2.63, 95% CI: 1.48-4.68).
Conclusion
ERAS® protocols for mastectomy patients with or without IBR are associated with decreases in chronic opioid use, without concomitant increases in chronic sedative use.
Background
Local anaesthetics are widely used for their analgesic and anaesthetic properties in the perioperative setting, including surgical procedures to excise malignant tumours. Simultaneously, chemotherapeutic agents remain a cornerstone of cancer treatment, targeting rapidly dividing cancer cells to inhibit tumour growth. The potential interactions between these two drug classes have drawn increasing attention and there are oncological surgical contexts where their combined use could be considered. This review examines existing evidence regarding the interactions between local anaesthetics and chemotherapeutic agents, including biological mechanisms and clinical implications.
Methods
A systematic search of electronic databases was performed as per Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Selection criteria were designed to capture in vitro, in vivo, and clinical studies assessing interactions between local anaesthetics and a wide variety of chemotherapeutic agents. Screening and data extraction were performed independently by two reviewers. The data were synthesised using a narrative approach because of the anticipated heterogeneity of included studies.
Results
Initial searches yielded 1225 relevant articles for screening, of which 43 met the inclusion criteria. The interactions between local anaesthetics and chemotherapeutic agents were diverse and multifaceted. In vitro studies frequently demonstrated altered cytotoxicity profiles when these agents were combined, with variations depending on the specific drug combination and cancer cell type. Mechanistically, some interactions were attributed to modifications in efflux pump activity, tumour suppressor gene expression, or alterations in cellular signalling pathways associated with tumour promotion. A large majority of in vitro studies report potentially beneficial effects of local anaesthetics in terms of enhancing the antineoplastic activity of chemotherapeutic agents. In animal models, the combined administration of local anaesthetics and chemotherapeutic agents showed largely beneficial effects on tumour growth, metastasis, and overall survival. Notably, no clinical study examining the possible interactions of local anaesthetics and chemotherapy on cancer outcomes has been reported.
Conclusions
Reported preclinical interactions between local anaesthetics and chemotherapeutic agents are complex and encompass a spectrum of effects which are largely, although not uniformly, additive or synergistic. The clinical implications of these interactions remain unclear because of the lack of prospective trials. Nonetheless, the modulation of chemotherapy effects by local anaesthetics warrants further clinical investigation in the context of cancer surgery where they could be used together.
Clinical trial registration
Open Science Framework (OSF, project link: https://osf.io/r2u4z)
Preclinical evidence indicates potent antitumor properties of local anesthetics. Numerous underlying mechanisms explaining such anticancer effects have been identified, suggesting direct cytotoxic as well as indirect immunemediated effects that together reduce the proliferative, invasive and migratory potential of malignant cells. Although some retrospective and correlative studies support these findings, prospective randomized controlled trials have not yet fully confirmed the antineoplastic activity of local anesthetics, likely due to the intricate methodology required for mitigating confounding factors. This trial watch aims at compiling all published preclinical and clinical research, along with completed and ongoing trials, that explore the potential antitumor effects of local anesthetics.
The incidence of breast cancer is increasing rapidly in urban India due to the changing lifestyle and exposure to risk factors. Diagnosis at an advanced stage and in younger women are the most concerning issues of breast cancer in India. Lack of awareness and social taboos related to cancer diagnosis make women feel hesitant to seek timely medical advice. As almost half of women develop breast cancer at an age younger than 50 years, breast cancer diagnosis poses a huge financial burden on the household and impacts the entire family. Moreover, inaccessibility, unaffordability, and high out-of-pocket expenditure make this situation grimmer. Women find it difficult to get quality cancer care closer to their homes and end up traveling long distances for seeking treatment. Significant differences in the cancer epidemiology compared to the west make the adoption of western breast cancer management guidelines challenging for Indian women. In this article, we intend to provide a comprehensive review of the management of breast cancer from diagnosis to treatment for both early and advanced stages from the perspective of low-middle-income countries. Starting with a brief introduction to epidemiology and guidelines for diagnostic modalities (imaging and pathology), treatment has been discussed for early breast cancer (EBC), locally advanced, and MBC. In-depth information on loco-regional and systemic therapy has been provided focusing on standard treatment protocols as well as scenarios where treatment can be de-escalated or escalated.
Surgery exposes tumor tissue to severe hypoxia and mechanical stress leading to rapid gene expression changes in the tumor and its microenvironment, which remain poorly characterized. We biopsied tumor and adjacent normal tissues from patients with breast (n = 81) and head/neck squamous cancers (HNSC; n = 10) at the beginning (A), during (B), and end of surgery (C). Tumor/normal RNA from 46/81 patients with breast cancer was subjected to mRNA-Seq using Illumina short-read technology, and from nine patients with HNSC to whole-transcriptome microarray with Illumina BeadArray. Pathways and genes involved in 7 of 10 known cancer hallmarks, namely, tumor-promoting inflammation (TNF-A, NFK-B, IL18 pathways), activation of invasion and migration (various extracellular matrix–related pathways, cell migration), sustained proliferative signaling (K-Ras Signaling), evasion of growth suppressors (P53 signaling, regulation of cell death), deregulating cellular energetics (response to lipid, secreted factors, and adipogenesis), inducing angiogenesis (hypoxia signaling, myogenesis), and avoiding immune destruction (CTLA4 and PDL1) were significantly deregulated during surgical resection (time points A vs. B vs. C). These findings were validated using NanoString assays in independent pre/intra/post-operative breast cancer samples from 48 patients. In a comparison of gene expression data from biopsy (analogous to time point A) with surgical resection samples (analogous to time point C) from The Cancer Genome Atlas study, the top deregulated genes were the same as identified in our analysis, in five of the seven studied cancer types. This study suggests that surgical extirpation deregulates the hallmarks of cancer in primary tumors and adjacent normal tissue across different cancers.
Implications
Surgery deregulates hallmarks of cancer in human tissue.
The major goal of translational research is to evaluate the efficacy and effectiveness of treatments and interventions that have emerged from exhaustive preclinical evidence. In 2007, a major clinical trial was started to investigate the impact of paravertebral analgesia on breast cancer recurrence. The trial was based on preclinical evidence demonstrating that spinal anesthesia suppressed metastatic dissemination by inhibiting surgical stress, boosting the immunological response, avoiding volatile anesthetics, and reducing opioid use. However, that trial and three more recent randomized trials with a total of 4,770 patients demonstrate that regional analgesia does not improve survival outcomes after breast, lung, and abdominal cancers. An obvious question is why there was an almost complete disconnect between the copious preclinical investigations suggesting benefit and robust clinical trials showing no benefit? The answer is complex but may result from preclinical research being mechanistically driven and based on reductionist models. Both basic scientists and clinical investigators underestimated the limitations of various preclinical models, leading to the apparently incorrect hypothesis that regional anesthesia reduces cancer recurrence. This article reviews factors that contributed to the discordance between the laboratory science, suggesting that regional analgesia might reduce cancer recurrence and clinical trials showing that it does not—and what can be learned from the disconnect.
The disparity in access to and quality of surgical cancer care between high and low resource settings impacts immediate and long‐term oncological outcomes. With cancer incidence and mortality set to increase rapidly in the next few decades, we examine the factors leading to inequities in global cancer surgery, and look at potential solutions to overcome these challenges.
Ion channels are key signaling proteins found throughout the body; they are critical in many, wide-ranging physiological processes, from gene expression, sensory perception and processing to the cardiac action potential. When ion channel activity goes awry, for example, via mutation, damage or disrupted homeostasis, the outcome can result in causation, development and/or maintenance of disease. Ion channel dependent diseases have been dubbed channelopathies. Recent studies on the role of ion channels in cancer biology suggest that cancer is one such channelopathy. Many ion channels have now been implicated in the cellular processes that are affected in a multitude of cancers. In the last two decades, the field of ion channel and cancer research has been growing exponentially: a combination of developments in molecular biology, genetics, electrophysiology and automation have driven an explosion in our capabilities to interrogate ion channel pathways; how, why and where they go wrong and therapeutic interventions to correct their pathophysiology in cancer. A review of this vast and rapidly developing field would require a titanic tome to merely dimple the surface of research that has ballooned recently. In lieu of that huge undertaking—for the benefit of both authors and readers - this review discusses select examples of primary, applied and clinical research, aiming to shine a light on some of the more innovative and novel findings that this exciting field is excavating.
The use of local anesthetics during surgical treatment of cancer patients is an important part of perioperative analgesia. In recent years, it has been showed that local anesthetics can directly or indirectly affect the progression of tumors. In vitro and in vivo studies have demonstrated that local anesthetics reduced cancer recurrence. The etiology of this effect is likely multifactorial. Numerous mechanisms were proposed based on the local anesthetic used and the type of cancer. Mechanisms center on NaV1.5 channels, Ras homolog gene family member A, cell cycle, endothelial growth factor receptor, calcium Influx, microRNA and mitochondrial, in combination with hyperthermia and transient receptor potential melastatin 7 channels. Local anesthetics significantly decrease the proliferation of cancers, including ovarian, breast, prostate, thyroid, colon, glioma, and histiocytic lymphoma cell cancers, by activating cell death signaling and decreasing survival pathways. We also summarized clinical evidence and randomized trial data to confirm that local anesthetics inhibited tumor progression.
Voltage-gated sodium (NaV) channels, initially characterized in excitable cells, have been shown to be aberrantly expressed in non-excitable cancer tissues and cells from epithelial origins such as in breast, lung, prostate, colon, cervix, while they are not expressed in cognate non-cancer tissues. Their activity was demonstrated to promote aggressive and invasive potencies of cancer cells, both in vitro and in vivo, while their deregulated expression in cancer tissues has been associated with metastatic progression and cancer-related death. This review proposes NaV channels as pharmacological targets for anticancer treatments providing opportunities for repurposing existing NaV-inhibitors or developing new pharmacological and nutritional interventions.
This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2‐fold to 3‐fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2‐fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
While cancer treatment has improved dramatically, it has also encountered many critical challenges, such as disease recurrence, metastasis, and drug resistance, making new drugs with novel mechanisms an urgent clinical need. The term “drug repositioning,” also known as old drugs for new uses, has emerged as one practical strategy to develop new anticancer drugs. Anesthetics have been widely used in surgical procedures to reduce the excruciating pain. Lidocaine, one of the most-used local anesthetics in clinical settings, has been found to show multi-activities, including potential in cancer treatment. Growing evidence shows that lidocaine may not only work as a chemosensitizer that sensitizes other conventional chemotherapeutics to certain resistant cancer cells, but also could suppress cancer cells growth by single use at different doses or concentrations. Lidocaine could suppress cancer cell growth in vitro and in vivo via multiple mechanisms, such as regulating epigenetic changes and promoting pro-apoptosis pathways, as well as regulating ABC transporters, metastasis, and angiogenesis, etc., providing valuable information for its further application in cancer treatment and for new drug discovery. In addition, lidocaine is now under clinical trials to treat certain types of cancer. In the current review, we summarize the research and analyze the underlying mechanisms, and address key issues in this area.
Ion channels can regulate the plasma membrane potential (Vm) and cell migration as a result of altered ion flux. However, the mechanism by which Vm regulates motility remains unclear. Here, we show that the Nav1.5 sodium channel carries persistent inward Na+ current which depolarizes the resting Vm at the timescale of minutes. This Nav1.5‐dependent Vm depolarization increases Rac1 colocalization with phosphatidylserine, to which it is anchored at the leading edge of migrating cells, promoting Rac1 activation. A genetically encoded FRET biosensor of Rac1 activation shows that depolarization‐induced Rac1 activation results in acquisition of a motile phenotype. By identifying Nav1.5‐mediated Vm depolarization as a regulator of Rac1 activation, we link ionic and electrical signaling at the plasma membrane to small GTPase‐dependent cytoskeletal reorganization and cellular migration. We uncover a novel and unexpected mechanism for Rac1 activation, which fine tunes cell migration in response to ionic and/or electric field changes in the local microenvironment. Ion channels can regulate the plasma membrane potential (Vm) and cell migration as a result of altered ion flux. We show that the Nav1.5 sodium channel depolarizes the resting Vm, promoting Rac1 activation at the leading edge of migrating cells. By identifying Nav1.5‐mediated Vm depolarization as a regulator of Rac1 activation, we link ionic and electrical signaling at the plasma membrane to small GTPase‐dependent cytoskeletal reorganization and cellular migration.
Surgical procedures such as tumor resection and biopsy are still the gold standard for diagnosis and (determination of) treatment of solid tumors, and are prognostically beneficial for patients. However, growing evidence suggests that even a minor surgical trauma can influence several (patho) physiological processes that might promote postoperative metastatic spread and tumor recurrence. Local effects include tumor seeding and a wound healing response that can promote tumor cell migration, proliferation, differentiation, extracellular matrix remodeling, angiogenesis and extravasation. In addition, local and systemic immunosuppression impairs antitumor immunity and contributes to tumor cell survival. Surgical manipulation of the tumor can result in cancer cell release into the circulation, thus increasing the chance of tumor cell dissemination. To prevent these undesired effects of surgical interventions, therapeutic strategies targeting immune response exacerbation or alteration have been proposed. This review summarizes the current literature regarding these local, systemic and secondary site effects of surgical interventions on tumor progression and dissemination, and discusses studies that aimed to identify potential therapeutic approaches to prevent these effects in order to further increase the clinical benefit from surgical procedures.
Background: Hypoxia is defined as oxygen levels in tumor microenvironment of less than that in blood (90-100 mm Hg) and influences many aspects of tumour biology. During surgery tumour vasculature is cut off gradually leading to induction of acute hypoxia.The present study aims to experimentally test the genotypic and phenotypic effects of surgically induced acute hypoxia in breast cancer tumor samples and cell lines.
Methodology: Core biopsy samples were collected from breast tumors (N=8 patients) at three time points during their curative surgery: prior (pre), mid-way (intra) and at the end (post). The samples were subjected to RNA-Seq and a list of differentially expressed genes (DEG) was prepared. A set of 26 DEG (‘pre’ Vs ‘intra’ Vs ‘post’) obtained from RNA-Seq analysis and additional 17 genes involved in inflammation, EMT and hypoxia pathways were chosen for validation in tumor samples. These genes were validated using a customized qPCR Array (Qiagen). A gene was considered validated if it was significantly deregulated in at least 4 out of 8 patients. In another experiment, MCF-7 cells were exposed to varying levels of oxygen concentrations (0.1-20%) for varying time periods ranging from 30 minutes to 72 hours, to study time and dose dependent effects of hypoxia on following functional characteristics: proliferation, invasion and cell cycle changes.
Results: Concordant, statistically significant up-regulation of FOS, DUSP1, JUNB, FOSB, ZFP36, RGS1, S100A4, CXCL8 and CCL2 were observed in RNA-Seq and qPCR experiments while MMP13, HIF1A and VEGFA were up-regulated only in qPCR. However, 7 protein markers of inflammation, EMT and hypoxia did not show any significant change between pre, intra and post-operative samples. In MCF-7 cells, a dose and time dependent decrease in cell viability was observed with increasing severity of hypoxia as well as decrease in invasiveness, but there was no significant impact on cell cycle phases. When hypoxic cells were re-incubated under normoxic conditions an increase in cell proliferation and accumulation of cells in S phase (with a reduction in G2-M fraction) were observed, compared to cells grown under only normoxic conditions.
Conclusion: Acute intra-operative hypoxia up-regulates expression of genes related to cell survival, chemoresistance, invasiveness, inflammation and angiogenesis in breast tumors. Breast cancer cells exposed to acute severe hypoxia followed by normoxia show increased proliferation. These effects may have implications for tumor cells that disseminate during surgery.
Citation Format: Dimple R. Bhatia, Shalaka Joshi, Rohan Chaubal, Poonam Gera, Prajakta Kalkar, Farheen Naeem, Nisanth Mathew Raju, Nilesh Gardi, Nita Nair, Vaibhav Vanmali, Rohini W. Hawaldar, Amit Dutt, Rajendra A. Badwe, Sudeep Gupta. The effect of acute intraoperative hypoxia in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4524. doi:10.1158/1538-7445.AM2017-4524
Surgery is a crucial intervention and provides a chance of cure for patients with cancer. The perioperative period is characterized by an increased risk for accelerated growth of micrometastatic disease and increased formation of new metastatic foci. The true impact for cancer patients remains unclear. This review summarizes the often fragmentary clinical and experimental evidence supporting the role of surgery and inflammation as potential triggers for disease recurrence. Surgery induces increased shedding of cancer cells into the circulation, suppresses antitumor immunity allowing circulating cells to survive, upregulates adhesion molecules in target organs, recruits immune cells capable of entrapping tumor cells, and induces changes in the target tissue and in the cancer cells themselves to enhance migration and invasion to establish at the target site. Surgical trauma induces local and systemic inflammatory responses that can also contribute to the accelerated growth of residual and micrometastatic disease. Furthermore, we address the role of perioperative factors, including anesthesia, transfusions, hypothermia, and postoperative complications, as probable deleterious factors contributing to early recurrence. Through the admittedly limited understanding of these processes, we will attempt to provide suggestions for potential new therapeutic approaches to target the protumorigenic perioperative window and ultimately improve long-term oncological outcomes. Cancer Res; 77(7); 1-5. ©2017 AACR.
Many nonrandomized studies have suggested better outcome for patients with breast cancer who undergo surgery during the luteal (progestogenic) phase of their menstrual cycle, but this is controversial. We investigated the effect of a single preoperative injection of hydroxyprogesterone in women with operable breast cancer (OBC) in a randomized controlled trial (ClinicalTrials.gov identifier, NCT00123669).
One thousand patients with OBC were randomly assigned to receive surgery or an intramuscular injection of depot hydroxyprogesterone 500 mg 5 to 14 days before surgery. Primary and secondary end points were disease-free survival (DFS) and overall survival (OS), respectively. An analysis by axillary lymph node status was preplanned.
At a median follow-up of 65 months among 976 eligible patients, 273 recurrences and 202 deaths were recorded. In the progesterone group versus control group, 5-year DFS and OS rates were 73.9% v 70.2% (hazard ratio [HR], 0.87; 95% CI, 0.68 to 1.09; P = .23) and 80.2% v 78.4% (HR, 0.92; 95% CI, 0.69 to 1.21; P = .53), respectively. In 471 node-positive patients, the 5-year DFS and OS rates in the progesterone group versus control group were 65.3% v 54.7% (HR, 0.72; 95% CI, 0.54 to 0.97; P = .02) and 75.7% v 66.8% (HR, 0.70; 95% CI, 0.49 to 0.99; P = .04), respectively. In multivariate analysis, DFS was significantly improved with progesterone in node-positive patients (adjusted HR, 0.71; 95% CI, 0.53 to 0.95; P = .02), whereas there was no significant effect in node-negative patients (P for interaction = .04).
A single injection of hydroxyprogesterone before surgery did not improve outcomes in all women with OBC. This intervention showed significant improvement in node-positive women that may be considered hypothesis generating. If replicated in other studies, this could be a simple and inexpensive intervention, especially in developing countries where the incidence of lymph node metastasis is high.
Ion channel activity is involved in several basic cellular behaviors that are integral to metastasis (e.g., proliferation, motility, secretion, and invasion), although their contribution to cancer progression has largely been ignored. The purpose of this study was to investigate voltage-gated Na(+) channel (VGSC) expression and its possible role in human breast cancer.
Functional VGSC expression was investigated in human breast cancer cell lines by patch clamp recording. The contribution of VGSC activity to directional motility, endocytosis, and invasion was evaluated by in vitro assays. Subsequent identification of the VGSC alpha-subunit(s) expressed in vitro was achieved using reverse transcription-PCR, immunocytochemistry, and Western blot techniques and used to investigate VGSCalpha expression and its association with metastasis in vivo.
VGSC expression was significantly up-regulated in metastatic human breast cancer cells and tissues, and VGSC activity potentiated cellular directional motility, endocytosis, and invasion. Reverse transcription-PCR revealed that Na(v)1.5, in its newly identified "neonatal" splice form, was specifically associated with strong metastatic potential in vitro and breast cancer progression in vivo. An antibody specific for this form confirmed up-regulation of neonatal Na(v)1.5 protein in breast cancer cells and tissues. Furthermore, a strong correlation was found between neonatal Na(v)1.5 expression and clinically assessed lymph node metastasis.
Up-regulation of neonatal Na(v)1.5 occurs as an integral part of the metastatic process in human breast cancer and could serve both as a novel marker of the metastatic phenotype and a therapeutic target.
PURPOSE
Distant metastases are present in 6% or more of patients with newly diagnosed breast cancer. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival (OS), but clinical trials have reported conflicting results.
METHODS
Women presenting with metastatic breast cancer and an intact primary tumor received systemic therapy for 4-8 months; if no disease progression occurred, they were randomly assigned to locoregional therapy for the primary site (surgery and radiotherapy per standards for nonmetastatic disease) or continuing sysmetic therapy. The primary end point was OS; locoregional control and quality of life were secondary end points. The trial design provided 85% power to detect a 19.3% absolute difference in the 3-year OS rate in randomly assigned patients. The stratified log-rank test and Cox proportional hazards model were used to compare OS between arms. Cumulative incidence of locoregional progression was compared using Gray's test. Quality-of-life assessment used standard instruments.
RESULTS
Of 390 participants enrolled, 256 were randomly assigned: 131 to continued systemic therapy and 125 to early locoregional therapy. The 3-year OS was 67.9% without and 68.4% with early locoregional therapy (hazard ratio = 1.11; 90% CI, 0.82 to 1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9 to not estimable) in the systemic therapy arm and 54.9 months (95% CI, 46.7 to not estimable) in the locoregional therapy arm. Locoregional progression was less frequent in those randomly assigned to locoregional therapy (3-year rate: 16.3% v 39.8%; P < .001). Quality-of-life measures were largely similar between arms.
CONCLUSION
Early locoregional therapy for the primary site did not improve survival in patients presenting with metastatic breast cancer. Although it was associated with improved locoregional control, this had no overall impact on quality of life.
Background:
Three perioperative factors impair host defence against recurrence during cancer surgery: the surgical stress response, use of volatile anaesthetic, and opioids for analgesia. All factors are ameliorated by regional anaesthesia-analgesia. We tested the primary hypothesis that breast cancer recurrence after potentially curative surgery is lower with regional anaesthesia-analgesia using paravertebral blocks and the anaesthetic propofol than with general anaesthesia with the volatile anaesthetic sevoflurane and opioid analgesia. A second hypothesis was that regional anaesthesia-analgesia reduces persistent incisional pain.
Methods:
We did a randomised controlled trial at 13 hospitals in Argentina, Austria, China, Germany, Ireland, New Zealand, Singapore, and the USA. Women (age <85 years) having potentially curative primary breast cancer resections were randomised by computer to either regional anaesthesia-analgesia (paravertebral blocks and propofol) or general anaesthesia (sevoflurane) and opioid analgesia. The primary outcome was local or metastatic breast cancer recurrence. The secondary outcome was incisional pain at 6 months and 12 months. Primary analyses were done under intention-to-treat principles. This trial is registered with ClinicalTrials.gov, NCT00418457. The study was stopped after a preplanned futility boundary was crossed.
Findings:
Between Jan 30, 2007, and Jan 18, 2018, 2132 women were enrolled to the study, of whom 24 were excluded before surgery. 1043 were assigned to regional anaesthesia-analgesia and 1065 were allocated to general anaesthesia. Baseline characteristics were well balanced between study groups. Median follow-up was 36 (IQR 24-49) months. Among women assigned regional anaesthesia-analgesia, 102 (10%) recurrences were reported, compared with 111 (10%) recurrences among those allocated general anaesthesia (hazard ratio 0·97, 95% CI 0·74-1·28; p=0·84). Incisional pain was reported by 442 (52%) of 856 patients assigned to regional anaesthesia-analgesia and 456 (52%) of 872 patients allocated to general anaesthesia at 6 months, and by 239 (28%) of 854 patients and 232 (27%) of 852 patients, respectively, at 12 months (overall interim-adjusted odds ratio 1·00, 95% CI 0·85-1·17; p=0·99). Neuropathic breast pain did not differ by anaesthetic technique and was reported by 87 (10%) of 859 patients assigned to regional anaesthesia-analgesia and 89 (10%) of 870 patients allocated to general anaesthesia at 6 months, and by 57 (7%) of 857 patients and 57 (7%) of 854 patients, respectively, at 12 months.
Interpretation:
In our study population, regional anaesthesia-analgesia (paravertebral block and propofol) did not reduce breast cancer recurrence after potentially curative surgery compared with volatile anaesthesia (sevoflurane) and opioids. The frequency and severity of persistent incisional breast pain was unaffected by anaesthetic technique. Clinicians can use regional or general anaesthesia with respect to breast cancer recurrence and persistent incisional pain.
Funding:
Sisk Healthcare Foundation (Ireland), Eccles Breast Cancer Research Fund, British Journal of Anaesthesia International, College of Anaesthetists of Ireland, Peking Union Medical College Hospital, Science Fund for Junior Faculty 2016, Central Bank of Austria, and National Healthcare Group.
Background:
Conflicting evidence exists regarding the value of surgical resection of the primary in stage IV breast cancer patients.
Objective:
The prospective randomized phase III ABCSG-28 POSYTIVE trial evaluated median survival comparing primary surgery followed by systemic therapy to primary systemic therapy in de novo stage IV breast cancer.
Methods:
Between 2011 and 2015, 90 previously untreated stage IV breast cancer patients were randomly assigned to surgical resection of the primary tumor followed by systemic therapy (Arm A) or primary systemic therapy (Arm B) in Austria. Overall survival (OS) was defined as the primary study endpoint.
Results:
The trial was stopped early due to poor recruitment. Ninety patients (45 arm A, 45 arm B) were included; median follow-up was 37.5 months. Patients in the surgery arm had more cT3 breast cancer (22.2% vs 6.7%) and more cN2 staging (15.6% vs 4.4%). Both groups were well balanced with respect to the type of first-line systemic treatment. Median survival in arm A was 34.6 months, versus 54.8 months in the nonsurgery arm [hazard ratio (HR) 0.691, 95% confidence interval (95% CI) 0.358-1.333; P = 0.267]; time to distant progression was 13.9 months in the surgery arm and 29.0 months in the nonsurgery arm (HR 0.598, 95% CI 0.343-1.043; P = 0.0668).
Conclusion:
The prospective phase III trial ABCSG-28 (POSYTIVE) could not demonstrate an OS benefit for surgical resection of the primary in breast cancer patients presenting with de novo stage IV disease.
Surgery remains the primary treatment for patients with solid tumours, yet postoperative locoregional recurrence and distant metastasis occur frequently and confer high risks of morbidity and mortality
Deleterious effects of surgery include the initiation of local and/or systemic inflammation, increased catecholamine levels, immunosuppression, a prothrombotic state, and exposure to anaesthetic agents; these processes overlap with cancer-promoting signalling pathways
Cancer cells that escape resection are subject to perioperative physiological changes and might disseminate and colonize distant organs, thus contributing to postoperative cancer recurrence
Perioperative use of β-adrenoceptor antagonists, anti-inflammatory drugs, intravenous anaesthetics, and antithrombotic agents is linked with improved survival outcomes in patients with cancer
>60% of patients with cancer are treated with surgery; therefore, offsetting the deleterious effects of surgery by use of affordable and readily available therapies might rapidly improve the postoperative survival of patients with cancer
Background:
The role of locoregional treatment in women with metastatic breast cancer at first presentation is unclear. Preclinical evidence suggests that such treatment might help the growth of metastatic disease, whereas many retrospective analyses in clinical cohorts have suggested a favourable effect of locoregional treatment in these patients. We aimed to compare the effect of locoregional treatment with no treatment on outcome in women with metastatic breast cancer at initial presentation.
Methods:
In this open-label, randomised controlled trial, we recruited previously untreated patients (≤65 years of age with an estimated remaining life expectancy of at least 1 year) presenting with de-novo metastatic breast cancer from Tata Memorial Centre, Mumbai, India. Patients were randomly assigned (1:1) to receive locoregional treatment directed at their primary breast tumour and axillary lymph nodes, or no locoregional treatment, by a computer-generated block randomisation sequence (block size of four). Randomisation was stratified by site of distant metastases, number of metastatic lesions, and hormone receptor status. Patients with resectable primary tumour in the breast that could be treated with endocrine therapy were randomly assigned upfront, whereas those with an unresectable primary tumour were planned for chemotherapy before randomisation. Of the patients who had chemotherapy before randomisation, we randomly assigned patients who had an objective tumour response after six to eight cycles of chemotherapy. The primary endpoint was overall survival analysed by intention to treat. This study is registered with ClinicalTrials.gov, NCT00193778.
Findings:
Between Feb 7, 2005, and Jan 18, 2013, of the 716 women presenting with de-novo metastatic breast cancer, we randomly assigned 350 patients: 173 to locoregional treatment and 177 to no locoregional treatment. At data cut-off of Nov 1, 2013, median follow-up was 23 months (IQR 12·2-38·7) with 235 deaths (locoregional treatment n=118, no locoregional treatment n=117). Median overall survival was 19·2 months (95% CI 15·98-22·46) in the locoregional treatment group and 20·5 months (16·96-23·98) in the no-locoregional treatment group (HR 1·04, 95% CI 0·81-1·34; p=0·79), and the corresponding 2-year overall survival was 41·9% (95% CI 33·9-49·7) in the locoregional treatment group and 43·0% (35·2-50·8) in the no locoregional treatment group. The only adverse event noted was wound infection related to surgery in one patient in the locoregional treatment group.
Interpretation:
There is no evidence to suggest that locoregional treatment of the primary tumour affects overall survival in patients with metastatic breast cancer at initial presentation who have responded to front-line chemotherapy, and this procedure should not be part of routine practice.
Retrospective analysis of patients undergoing cancer surgery suggests the use of regional anesthesia may reduce cancer recurrence and improve survival. Amide-linked local anesthetics have antiinflammatory properties, although the mechanism of action in this regard is unclear. As inflammatory processes involving Src tyrosine protein kinase and intercellular adhesion molecule-1 are important in tumor growth and metastasis, we hypothesized that amide-linked local anesthetics may inhibit inflammatory Src-signaling involved in migration of adenocarcinoma cells.
NCI-H838 lung cancer cells were incubated with tumor necrosis factor-α in absence/presence of ropivacaine, lidocaine, or chloroprocaine (1 nM-100 μM). Cell migration and total cell lysate Src-activation and intercellular adhesion molecule-1 phosphorylation were assessed. The role of voltage-gated sodium-channels in the mechanism of local anesthetic effects was also evaluated.
Ropivacaine treatment (100 μM) of H838 cells for 20 min decreased basal Src activity by 62% (P=0.003), and both ropivacaine and lidocaine coadministered with tumor necrosis factor-α statistically significantly decreased Src-activation and intercellular adhesion molecule-1 phosphorylation, whereas chloroprocaine had no such effect. Migration of these cells at 4 h was inhibited by 26% (P=0.005) in presence of 1 μM ropivacaine and 21% by 1 μM lidocaine (P=0.004). These effects of ropivacaine and lidocaine were independent of voltage-gated sodium-channel inhibition.
This study indicates that amide-, but not ester-linked, local anesthetics may provide beneficial antimetastatic effects. The observed inhibition of NCI-H838 cell migration by lidocaine and ropivacaine was associated with the inhibition of tumor necrosis factor-α-induced Src-activation and intercellular adhesion molecule-1 phosphorylation, providing the first evidence of a molecular mechanism that appears to be independent of their known role as sodium-channel blockers.
Regional anesthesia and analgesia attenuate or prevent perioperative factors that favor minimal residual disease after removal of the primary carcinoma. Therefore, the authors evaluated prostate cancer recurrence in patients who received either general anesthesia with epidural anesthesia/analgesia or general anesthesia with postoperative opioid analgesia.
In a retrospective review of medical records, patients with invasive prostatic carcinoma who underwent open radical prostatectomy between January 1994 and December 2003 and had either general anesthesia-epidural analgesia or general anesthesia-opioid analgesia were evaluated through October 2006. The endpoint was an increase in postoperative prostate-specific antigen.
After adjusting for tumor size, Gleason score, preoperative prostate-specific antigen, margin, and date of surgery, the epidural plus general anesthesia group had an estimated 57% (95% confidence interval, 17-78%) lower risk of recurrence compared with the general anesthesia plus opioids group, with a corresponding hazard ratio of 0.43 (95% confidence interval, 0.22-0.83; P = 0.012) in a multivariable Cox regression model. Gleason score and tumor size (percent of prostate involved) were also independent predictors of recurrence (hazards ratios of 1.19 [1.08, 1.52], P = 0.004, and 1.17 [1.03, 1.34] for 10% size difference, P = 0.01, respectively). A similar association between epidural use and recurrence was obtained by comparing patients matched on the propensity to receive epidural versus general anesthesia.
Open prostatectomy surgery with general anesthesia, substituting epidural analgesia for postoperative opioids, was associated with substantially less risk of biochemical cancer recurrence. Prospective randomized trials to evaluate this association seem warranted.
To compare long term recurrence of cancer and survival of patients having major abdominal surgery for cancer.
Long term follow-up of prospective randomised controlled clinical trial in which patients were randomly assigned to receive general anaesthesia with or without epidural block for at least three postoperative days. Setting 23 hospitals in Australia, New Zealand, and Asia.
503 adult patients who had potentially curative surgery for cancer.
Cancer-free survival (analysis was by intention to treat).
Long term follow-up data were available for 94% (n=446) of eligible participants. The median time to recurrence of cancer or death was 2.8 (95% confidence interval 0.7 to 8.7) years in the control group and 2.6 (0.7 to 8.7) years in the epidural group (P=0.61). Recurrence-free survival was similar in both epidural and control groups (hazard ratio 0.95, 95% confidence interval 0.76 to 1.17; P=0.61).
Use of epidural block in abdominal surgery for cancer is not associated with improved cancer-free survival.
Australian New Zealand Clinical Trials Registry ACTRN12607000637448.
In cancer patients, dormant micrometastases are often asymptomatic and clinically undetectable, for months or years, until relapse. We have studied dormant lung metastases under angiogenesis suppression in mice. The metastases exhibited rapid growth when the inhibition of angiogenesis was removed. Tumour cell proliferation, as measured by bromodeoxyuridine incorporation and immunohistochemical staining proliferating cell nuclear antigen, was not significantly different in dormant and growing metastases. However, tumour cells of dormant metastases exhibited a more than threefold higher incidence of apoptosis. These data show that metastases remain dormant when tumour cell proliferation is balanced by an equivalent rate of cell death and suggest that angiogenesis inhibitors control metastatic growth by indirectly increasing apoptosis in tumour cells.
There is sufficient evidence to support both the hormonal influence on the outcome of breast cancer surgery and the SDA hypothesis. The SDA model produces a paradigm shift in the understanding of the natural history of breast cancer. It offers opportunities to try modifying a tumor's biological potential for metastasis (e.g., by tamoxifen, progesterone, antiprotease, or angiostatin) in the neoadjuvant setting. It continues to support the beneficial effects of detection and surgery early in the natural history of disease. It would be worthwhile to plan a trial comparing standard practice (unplanned surgery as the patient enrolls) with surgery during the luteal phase of the menstrual cycle in premenopausal women. Another possibility, based on studies of circulating progesterone, would be to compare primary progesterone treatment (for 4 to 10 days before surgery) with standard practice. Such a trial of primary progesterone is already under way, conducted by the Indian Breast Group. More than 200 patients have enrolled so far. The details of the trial are available from Clinical Research Secretariat, Tata Memorial Centre, Parel, Mumbai, India (e mail: tmho3@bom2.vsnl.in).
This work reports the finding of a unique fast inward sodium current (I(Na)) in MDA-MB-231 cells which is missing in MDA-MB-468 cells and in MCF-7 cells. This current is high-voltage-activated and displays a window current at the membrane potential of MDA-MB-231 cells. This current is blocked by high concentrations of tetrodotoxin (TTX). In MDA-MB-231 cells, which are the most invasive cells among the three cell lines tested, proliferation and migration were not sensitive to TTX while invasion was reduced by approximately 30%. These experiments suggest that I(Na) is involved in the invasion process, probably through its participation to the regulation of the intracellular sodium homeostasis.