Intraoperative opioids and disease-free survival in glioblastoma multiforme

doi:10.21203/rs.3.rs-3760133/v1

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Intraoperative opioids and disease-free survival in glioblastoma multiforme

https://doi.org/10.21203/rs.3.rs-3760133/v1

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Introduction: Glioblastoma multiforme (GBM) is a primary tumor of the Central Nervous System (CNS). It is one of the most aggressive tumors that can affect humans, with no cure so far and an extremely inverse prognosis, with an average survival ranging from 7 to 15 months. Recently, the role of opioids, either in stopping or stimulating tumor progression, has been demonstrated for both sides. The main objective of this study was to investigate the influence of intraoperative opioid use on the overall and disease-free survival of these patients.

Methods: This observational and retrospective study analyzed the medical records of 133 patients who underwent 167 surgical procedures for resection of Glioblastoma Multiforme. Inclusion and exclusion criteria were as follows: patients older than 18 years of age, of both sexes, and who had confirmed GBM. Patients who died in the postoperative period from causes unrelated to the underlying disease were excluded, as were those who did not have specific data on the medications used in the perioperative period in their records. The following outcomes were analyzed: age, preoperative and postoperative Karnofsky scale (KPS), duration of the surgical procedure, opioid doses, overall survival, disease-free survival, sex, and race. To verify the existence of a correlation between quantitative variables, the Spearman Test was applied; for categorical (qualitative) variables, the Chi-square Test was used. The Kruskal–Wallis test was used to evaluate the variance in means between groups. In addition, the log-rank test was used to evaluate survival between the groups. The significance level adopted for all tests was 5% (p≤0.05).

Results: Analysis of the correlation between total opioid dosage and the investigated variables showed that surgical duration and age at surgery were significantly correlated with total opioid dosage. There was no correlation between total opioid dosage and the overall and disease-free survival times of patients.

Conclusion: This study suggests that there is no relationship between the intraoperative opioid dose and overall and disease-free survival in patients undergoing surgical treatment for Glioblastoma Multiforme.

Gliomas are the most common primary tumors of the Central Nervous System (CNS) with a frequency of approximately 48%. Its annual incidence is approximately 6/100,000 individuals in the general population [1–3]. It originates from glial cells, astrocytes, and oligodendrocytes; thus, we have astrocytomas and oligodendrogliomas. These tumors were initially classified by the World Health Organization (WHO), according to their histological characteristics into grade II (diffuse astrocytoma or grade II; oligodendroglioma grade II; and oligoastrocytoma grade II), grade III (anaplastic astrocytoma or grade III; anaplastic oligodendroglioma or grade III; and anaplastic oligoastrocytoma or grade III), and grade IV, called Glioblastoma Multiforme (GBM) regardless of the originating cell lineage. The histological differences that define each grade are grade II, isolated cytological atypia; grade III, anaplasia and mitotic activity; and grade IV, microvascular proliferation and/or necrosis[3].

In the 2016 Classification of CNS Tumors by the World Health Organization (WHO), genetic-molecular evaluation became part of the nomenclature of these neoplasms because of its relevant prognostic value. Regarding gliomas, specifically GBM, it was the presence of isocitrate dehydrogenase (IDH) mutations 1 and 2 that became determinants in its denomination. Thus, in this update, we have the following designations: GBM-IDH wild-type, in which there was no mutation; GBM-IDH mutated; and GBM-NOS, in which it was not possible to establish the occurrence of the mutation[3].

In 2021, the WHO published a new classification for CNS tumors with an even greater influence on the genetic molecular profile, which has been shown to have a more significant weight in the prognosis of these neoplasms, especially gliomas. Thus, HDI has become essential for classifying gliomas as GBM. This tumor is inserted in a subgroup of gliomas now called "Adult Diffuse Gliomas", in which we have the subtypes: "Mutated IDH astrocytoma", "Mutated and 1p/19q-co deleted IDH oligodendroglioma", and "Wild-type IDH glioblastoma". This means that after the new classification in 2021, every GBM must have the wild-type IDH gene[4].

Glioblastoma Multiforme (GBM) is the most frequent histological subtype, classified as grade 4, and accounting for approximately 50% of cases with an annual incidence of 3/100,000. It is more common in men than in women[3, 5]It is more common in men, twice as common in whites than in blacks, and occurs more frequently in the elderly at the age of 65 years. It is one of the most aggressive tumors that can affect humans, with no cure to date and an extremely unfavorable prognosis, with an average survival of 7–15 months [1, 2].

The most effective treatment for GBM is maximal surgical resection with preservation of the patient's neurological function, followed by concomitant radiotherapy and chemotherapy. After the completion of radiotherapy, the patient was kept under chemotherapy for another year. The chemotherapeutic agent used was temozolomide (TMZ), an alkylating agent administered orally[2, 6].

The characteristics of GBM on Magnetic Resonance Imaging (MRI), which is the method of choice for this diagnosis, are well known: heterogeneous lesions with peripheral gadolinium enhancement, imprecisely defined, with a hypointense center due to intratumoral necrosis, and perilesional edema. On MRI spectroscopy and perfusion sequences, a choline peak and a "hot" lesion were observed. Elevated choline levels on spectroscopy signify a high rate of cell replication, suggesting a neoplasm. Perfusion analyzes the intensity of blood flow in the lesion and when elevated, it is called a "hot lesion" which is interpreted as a tumor with intense neovascularization[5].

Despite advances in imaging technology, GBM confirmation of GBM is still dependent on anatomopathological evaluation. Thus, surgery, in addition to being a fundamental part of treatment with an impact on prognosis, is essential for diagnosis [2, 6].

It is a fact that the surgical procedure "per se" induces significant organic stress that negatively impacts the immune system. Other factors also act as immunosuppressants in the preoperative period, such as pain, tumor tissue manipulation, corticosteroids, blood transfusions, and anesthetic and analgesic drugs. Opioids are known for their complex pharmacological interactions with immediate and medium-term adverse effects[7, 8].

Opioids act through their receptors, among which, µ, k, and δ are prominent. The µ-opioid receptor (ROM) is present in cells of the central nervous system (CNS), peripheral nervous system (PNS), and immunocytes. The relationship between these drugs and the immune system has been discussed in the literature, and studies have shown antagonistic actions depending on the type of opioid, dose, and route of administration [9–11].

Several studies have demonstrated the presence of ROM in tumor cells. The relationship between increased ROM expression in tumor cells and disease progression and spread has been demonstrated in malignant neoplasms of the esophagus, liver, lungs, and breasts [12, 13]. There is also evidence of the presence of opioid receptor µ in GBM cells [14, 15].

In neurooncology, multidisciplinary action is essential to achieve the best results. The performance of each specialty involved, such as neurosurgery, oncology, anesthesiology, pathology, radiology, radiotherapy, neurology, psychology, physiotherapy, and speech therapy, must be shared for the benefit of the patient. The relationship between anesthesiology and neurosurgery should be one of absolute trust, as the intervention of one will have direct consequences on the other. On the basis of these premises, this study was conceived.

In the early 21st century there was an explosion of deaths in the US population caused by opioid abuse which is termed "The Opioid Crisis"[16, 17]. Since then, there has been an increased interest in the scientific community regarding the various implications of these drugs, especially in oncology. Several articles in the literature have analyzed this relationship, including GBM, but no study has compared the dose of intraoperative opioids with patient prognosis.

The present study was a retrospective analysis of data from the medical records of patients diagnosed with GBM undergoing surgery. The primary objective was to investigate the correlation between intraoperative opioid dose with disease-free survival and the secondary objective was to determine the correlation between opioid dose and OS.

This was an observational and retrospective study that analyzed the medical records of 133 patients who underwent 167 surgical procedures for the resection of Glioblastoma Multiforme in two hospitals between 2012 and 2020.

Study Registration and Financing

This study was approved by our Ethics Committee. The work was carried out with the main author's resources without any funding or support.

Inclusion and Exclusion Criteria

Patients aged > 18 years, of both sexes, who underwent surgery for a brain tumor with anatomopathological confirmation of GBM were included. Patients who died in the postoperative period from causes unrelated to the underlying disease were excluded, as were those who did not have in their records specific data on the drugs used in the preoperative period.

Analyzed Variables

Disease-free survival was defined as the time between surgery and the first clinical and/or imaging sign indicating tumor regrowth, overall survival, the time between surgery and death, or the last care recorded in the medical record.

Regarding disease-free survival, in cases of patients who underwent more than one procedure, only the data from the first surgery were considered for DFS in patients who underwent more than one procedure. In the OS analysis of overall survival, the sum of the opioid doses used in each surgery was considered.

The following quantitative variables were analyzed: symptom onset (time between first symptoms and medical attention), age (at the time of surgery), Aronofsky scale (KPS) score[18] before and after surgery, duration of the surgical procedure, and intraoperative opioid doses (Fentanyl, Sufentanil, Morphine, and Remifentanil).

The doses of the different opioids were analyzed individually and converted into Fentanyl doses in the following proportions: 1µg of Fentanyl is equivalent to 0.1µg of Sufentanil, 1µg of Remifentanil or 66.6µg of Morphine. This was necessary to obtain statistically significant data, and fentanyl was chosen because it is present in most procedures.

The qualitative variables analyzed were sex, race, degree of surgical resection of the tumor, and clinical condition in the immediate postoperative period (better, worse, or maintained compared with the preoperative period).

Statistical Analysis

A descriptive analysis of the data was performed, presenting numerical measures (minimum value, maximum value, mean, standard deviation, and coefficient of variation) for quantitative variables and absolute and percentage frequencies for qualitative variables.

The chi-squared test was used to verify the existence of an association between pairs of categorical variables. To test the association of Opioid Dose with categorical variables, it was necessary to stratify the values into high, moderate, and low doses. To do this, the quartiles of the opioid doses were calculated. From the Lowest to the 1st Quartile (Low Doses), from 1st to 3rd Quartile (moderate doses), from 3rd Quartile to Maximum (high doses).

To verify the existence of a correlation between quantitative variables, Spearman's test was applied; for categorical (qualitative) variables, the Chi-square Test was used. The Kruskal–Wallis test was used to assess the variance of means between groups, and the Log-Rank Test was used to compare survival between groups. The significance level adopted for all tests was 5% (p ≤ 0.05).

This study included 133 patients (45 females, 33.8%) and 88 males (66.2%). The patients underwent 167 surgical procedures. Categorical variables related to the patient's condition were race, presence of epileptic seizures, headache, and neurological deficit at diagnosis. The Postoperative Evolution and the Extent of Surgical Resection were analyzed as qualitative variables (Table 1).

Table 1

– Demographic data of the patients included in the study
Item	Variable	Value
Race	White	101 (75.94%)
	Black	6 (4.51%)
	Brown	26 (19.55%)
	Total	133 (100.00%)
Gender	Female	45 (33.83%)
	Male	88 (66.17%)
	Total	133 (100.00%)
Epileptic seizure	Não	102 (76.69%)
	Sim	31 (23.31%)
	Total	133 (100.00%)
Headache	Não	59 (44.36%)
	Sim	74 (55.64%)
	Total	133 (100.00%)
Neurological Deficit	No	40 (30,9%)
	Yes	93(69,1%)
	Total	133 (100%)
Pos-surgical status	Sustained	88 (52.6%)
	Improved	42 (25.15%)
	Worsened	37 (22.16%)
	Total	167 (100.00%)
Type of resection	Biopsy	1 (0.60%)
	Partial	87 (52.10%)
	Total	79 (47.31%)
	Total	167 (100.00%)
Number of reoperations (For each patient)	0	103 (77.44%)
	1	26 (19.55%)
	2	4 (3.01%)
	Total	133 (100.00%)

Table 2

– Summary of the continuous variables of the study
Variable	Minimum	Maximum	Mean	Standard Deviation	Variation Coefficient
Age at Surgery	15,0	90,0	56,2	14,2	25,3
Survival (Days)	2,0	2417,0	228,1	325,7	142,8
Symptoms onset (Days)	0,0	1456,0	43,7	131,1	300,3
Karnofsky Pre (%)	0,2	100,0	45,6	40,3	88,4
Karnofsky Pós (%)	0,1	100,0	46,7	42,8	91,7
Surgical Time (min)	90,0	480,0	262,4	85,0	32,4
Disease-free survival (Days)	0,0	1440,0	156,2	191,6	122,7
Total Dosage of Opioids (µg/kg)	1,5	134,8	33,8	24,9	73,7

Table 3

Correlations between opioid dosage and other variables. Bold values indicate statistical significance.
Item	rho	p
Age at surgery	-0.26	0.003
Surgical Duration (min)	0.19	0.029
Karnofsky Pré	-0.16	0.059
Karnofsky Pós	-0.12	0.18
Symptoms onset (days)	-0.07	0.46
Survival (days)	-0.06	0.526
Disease-free survival (days)	0.06	0.552

Most patients presented with an initial symptom of some neurological deficit (69.1%) compared to other common signs and symptoms in brain tumors, such as headache (55.64%) and epileptic seizure (23.31%).

Regarding the variables related to surgery, most patients had clinical-neurological status maintained in the immediate postoperative period (52.7%) when compared to the preoperative conditions. There was a similarity in the frequency of partial and total surgical resections (52.1% and 47.3%, respectively), and only one patient underwent biopsy.

Regarding quantitative variables, the mean (from the minimum and maximum values), standard deviation, and coefficient of variation were calculated. We collected data on age (at the time of surgery), symptom onset (related to the date of the first visit), pre-and postoperative Karnofsky Performance Scale (KPS) scores, time of surgery, and total intraoperative opioid dose in fentanyl equivalent. The overall Survival (ST) and Disease-Free Survival (DFS) were also analyzed as quantitative variables.

The mean age of the patients was approximately 56 years, with a standard deviation of 14 (56.2 ± 14.2). Except for Surgical Time and Age at Surgery, all other quantitative variables were heterogeneous, with a coefficient of variation well above 30%, which is the threshold value to consider high dispersion.

Specifically, regarding the intraoperative opioid dose, we found that the coefficient of variation was above 73%, and that the mean was closer to the minimum value than to the maximum value. Most patients received doses between 31 and 60µg of fentanyl/Kg of weight. Only two patients received doses above 120µg/Kg.

Spearman's test was applied to verify the existence of a correlation between the Opioid Dose variable and the other quantitative variables.

The results showed a significant correlation only with Surgical Time and Age at Surgery (p = 0.029 and 0.003, respectively). In the former, the relationship was positive; that is, the longer the Surgical Time, the higher the Opioid Dose used.

The results of the chi-squared test in the association analysis between categorical variables and opioid doses did not reveal significant statistical values (p > 0.05). Moreover, when applying the Kruskal–Wallis test to assess the variance of the means between the Opioid Dose groups for both disease-free survival and overall survival, no significant difference was found (p > 0.05).

Finally, the Log-Rank Test was applied to assess the probability of disease-free survival between the opioid dose groups; no difference was found between the groups (p = 0.89). (Fig. 3).

This study brings another ingredient to the broad discussion on the relationship between opioids and cancer. This study is unprecedented in the literature in analyzing the interference of intraoperative opioid dose on survival in patients with Glioblastoma Multiforme. We obtained results that confirmed the lack of correlation between intraoperative opioid dose and overall survival and disease-free survival in patients with Glioblastoma Multiforme.

In a study similar to ours, Cata et al. analyzed the use of intraoperative opioids in 195 patients with Squamous Cell Carcinoma of the Larynx[19] and noted an association with worsened survival but with low clinical relevance. The same author similarly analyzed this possible relationship with Non-Small Cell Lung Cancer[20] in 901 patients and reported a decline in survival only in those with stage I disease, concluding that there is insufficient evidence to discontinue the use of opioids in these surgeries.

In 2010 Forget, P. et al. published an article in which they analyzed the influence of several intraoperative analgesics used in mastectomies for breast cancer on disease recurrence. The opioid analyzed in this study was sufentanil, which showed no interference with recurrence[21]. In a preclinical study in mice, Doornebal et al. concluded that morphine did not facilitate the progression and dissemination of lobular, invasive, and HER2 + breast cancer [22].

The perioperative period causes cancer patients to experience extreme immunological vulnerability owing to several factors, including surgical stress with the release of catecholamines and prostaglandins, resulting in intense inflammation, hypothermia, tissue damage, blood transfusions, nutritional imbalance, and the use of anesthetics and analgesics, among which opioids play a relevant role[23, 24].

The interaction of these drugs in the evolution of malignant neoplasms can occur in two ways: directly through opioid µ receptors (ROM) in tumor cells and indirectly by inhibiting the immune system. This interference may occur directly in immunocytes (which also express ROM) or through the hypothalamic-pituitary system[25].

Zhang et al. demonstrated that ROM is a risk factor for metastasis in esophageal squamous cell carcinoma[26]. Another in vitro study revealed that hepatocarcinoma cells showed reduced proliferation due to inhibition of the opioid receptor µ [27]. Singleton et al. analyzed histopathological samples of lung cancer from individuals with and without metastases and identified a significantly higher expression of ROM in the former, suggesting a direct effect of this receptor on tumor progression[28]. In lung cancer, Mathew et al. concluded in an in vitro study that opioids, through the evident increase in ROM in neoplastic cells, stimulate tumor growth, a fact that was opposed when methylnaltrexone, an opioid antagonist, was used.

In a basic study on mice with breast cancer, Nguyen et al. concluded that morphine promotes tumor growth by increasing ROM expression(DOORNEBAL et al., 2015). Moreover, in a study published in 2015, the authors listed several studies showing a direct relationship between increased expression of the µ receptor in tumor cells and tumor dissemination and studies showing the action of an opioid antagonist (methylnaltrexone) as an inhibitor of tumor growth[29]. Specifically, regarding opioid antagonists as possible therapeutic targets in the control of various types of malignancies, Belltall et al. published a review and found that most studies were preclinical; therefore, there is insufficient evidence for this conclusion[30].

Regarding the immune system, Forget et al. analyzed the interaction between various analgesics and individual conditions in rats. The animals were subjected to surgery (laparotomy), and the activity of natural killer (NK) cells, which are responsible for the first line of defense of cellular immunity, was quantified at various times during the perioperative period. Fentanyl, the only opioid included, was shown to be a major inhibitor of NK activity and the only drug with a propensity to increase the incidence of metastasis (clonidine and ketamine were also included in this analysis) [21]. In this context, Beilin et al. published a prospective randomized study of 40 patients who underwent surgery with high and low doses of fentanyl. Both groups showed impaired NK cell activity; however, the first group recovered this function much later[31].

Liang et al. reviewed the topic of opioids and immune function and concluded that publications show antagonistic actions of these drugs. In their final analysis, the authors reported that, in general, opioids at low doses over a short time tend to stimulate the immune system. Immunosuppressive effects are associated with high doses and prolonged exposure [32].

In contrast, Gaspani et al. concluded in a rat study that tramadol acts as an immunostimulator, increasing the activity of NK cells, which does not occur with morphine. Tramadol is a centrally acting analgesic with low affinity for the µreceptor (GASPANI et al., 2002). Analyzing the same drugs, Sacerdote et al. reported similar results in a clinical study of patients undergoing surgery for uterine cancer; tramadol had a stimulatory effect on the immune system, while morphine acted in the opposite way[11].

In an extensive review on the action of opioid receptors on the immune system, Eisenstein TK. reported that morphine acts as an immunosuppressant most of the time and that this action is blocked by opioid antagonists through ROM[34].

The interest of the scientific community in the various implications of opioids, besides the complexity of the pharmacokinetics of these drugs, was stimulated by the so-called "opioid crisis" that broke out in the United States in the early 1990s. At that time, the American population showed an alarming number of deaths due to the abuse of opioid drugs indiscriminately prescribed in that country. The combination of these negative factors - inhibition of the immune system, interference in the prognosis of malignant neoplasms, and the North American public health crisis–has led to increased research on opioid-free anesthesia and the advantages of regional anesthesia over general anesthesia[9, 17, 32].

In this line of investigation, Exadaktylos et al. retrospectively analyzed 129 patients with breast cancer regarding recurrence and metastases in two groups, one undergoing mastectomy with paravertebral anesthesia and analgesia combined with general anesthesia and the other with general anesthesia and analgesia with morphine. They obtained significantly positive results in the prognosis of the group with paravertebral anesthesia in the first 30 months of follow-up[35].

In a brief review on the subject, Sessler D. I. lists three factors related to the decline in cellular immunity resulting from cancer surgery: stress due to tissue injury, general anesthesia, and opioid analgesia. In his evaluation, based mainly on preclinical in vitro and in vivo studies, these factors generated both impaired cellular immunity and increased angiogenesis, favoring tumor recurrence. This tendency is minimized by locoregional anesthesia and opioid-free analgesia[36].

In another review, Snyder et al. reported the effects of several anesthetic and analgesic drugs used in general anesthesia on the immune system. Specifically, the authors emphasized the inhibition of NK cell activity induced by morphine and fentanyl. Antagonistically, tramadol promotes the stimulation of these cells, providing an antitumor action[37].

Bovill, in an editorial, warns that, even though the evidence is inconclusive and conflicting, the option of loco-regional anesthesia should be considered whenever possible, minimizing the use of opioids. His conclusion is based on several studies that suggest not only an immunosuppressive influence but also the possibility of inducing tumorigenesis provided by general anesthesia and analgesia with opioids[38].

Cata et al. published an extensive review on how regional anesthesia would benefit and how general anesthesia would be detrimental to patients undergoing cancer surgery. The article didactically illustrates the pro-and antitumor actions of several factors and drugs and concludes that there is still not enough evidence to state that regional anesthesia reduces the risk of recurrence after cancer surgery[39]. The same conclusion was published by a group of experienced authors from the College of Anesthesiologists of Ireland on the topic of cancer and anesthesia, in which, among other statements, they attested the intriguing relationship between the use of opioid anesthetics and prognosis after neuro-oncological surgery [40].

Regarding gliomas and anesthetic techniques, Sung et al. addressed the topic in a retrospective study of 230 patients undergoing first surgery for glioma divided into two groups: one undergoing scalp block with local anesthetic after induction of anesthesia and the other without block. The group with scalp block showed longer disease-free survival than the group without a block. Importantly, this study also included patients with Grade II and III gliomas(SUNG et al.2021). In this study, no interference of opioids on patient prognosis was observed.

In a comprehensive review of the influence of anesthetic and analgesic techniques on GBM progression, Privorotskiy et al. reported that opioids do not affect survival after surgery for this tumor[42].

Two in vitro studies reported the apoptotic effects of opioids on glioma cells. Xu et al. concluded that remifentanil induces apoptosis in glioma cells, and Brawanski et al. showed that high doses of D- and L-methadone have apoptotic effects on glioblastoma cells and interact with temozolomide, the main chemotherapeutic agent used in the treatment of GBM[43]. Friesen et al. reported that D-methadone, acting as a µ-receptor agonist, inhibited the growth of GBM cells[44].

Finally, a recently published review by Ramirez et al. revealed the controversial and inconclusive topic of opioids and cancer prognosis, showing that the relationship between these two entities holds both favorable and unfavorable results [45].

The present study suggests that there is no relationship between intraoperative opioid dose and overall, disease-free survival in patients undergoing surgical treatment for Glioblastoma Multiforme.

Ethical Approval

The study was approved by an ethics committee under the CAAE: 90795518.6.0000.5411 . All the patients provided informed consent for the use of their data in the present study.

Funding

No funding was received for this study.

Availability of data and materials

No data are available online; however, under reasonable request, the data can be shared by the author.

Grochans S, Cybulska AM, Simińska D, Korbecki J, Kojder K, Chlubek D, Baranowska-Bosiacka I (2022) Epidemiology of Glioblastoma Multiforme–Literature Review. Cancers (Basel). https://doi.org/10.3390/CANCERS14102412
Wykes V, Zisakis A, Irimia M, Ughratdar I, Sawlani V, Watts C (2021) Importance and Evidence of Extent of Resection in Glioblastoma. J Neurol Surg A Cent Eur Neurosurg 82:75–86
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131:803–820
Osborn AG, Louis DN, Poussaint TY, Linscott LL, Salzman KL (2022) The 2021 World Health Organization Classification of Tumors of the Central Nervous System: What Neuroradiologists Need to Know. Am J Neuroradiol 43:928–937
Lee EJ, Ahn KJ, Lee EK, Lee YS, Kim DB (2013) Potential role of advanced MRI techniques for the peritumoural region in differentiating glioblastoma multiforme and solitary metastatic lesions. Clin Radiol 68:e689–e697
Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N Engl J Med 352:987–996
Sekandarzad MW, van Zundert AAJ, Lirk PB, Doornebal CW, Hollmann MW (2017) Perioperative Anesthesia Care and Tumor Progression. Anesth Analg 124:1697–1708
Vallejo R, de Leon-Casasola O, Benyamin R (2004) Opioid therapy and immunosuppression: a review. Am J Ther 11:354–365
Lisowska B, Jakubiak J, Siewruk K, Sady M, Kosson D (2020) Which idea is better with regard to immune response? Opioid anesthesia or opioid free anesthesia. J Inflamm Res 13:859–869
Page GG, Mcdonald JS, Ben-Eliyahu S (1998) Pre-operative versus postoperative administration of morphine: impact on the neuroendocrine, behavioural, and metastatic-enhancing effects of surgery. Br J Anaesth 81:216–223
Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A, Terno G, Ammatuna M, Panerai AE (2000) The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesth Analg 90:1411–1414
Lennon FE, Mirzapoiazova T, Mambetsariev B, Poroyko VA, Salgia R, Moss J, Singleton PA (2014) The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT) in human lung cancer. PLoS ONE. https://doi.org/10.1371/JOURNAL.PONE.0091577
Levins KJ, Prendeville S, Conlon S, Buggy DJ (2018) The effect of anesthetic technique on µ-opioid receptor expression and immune cell infiltration in breast cancer. J Anesth 32:792–796
Brawanski K, Brockhoff G, Hau P, Vollmann-Zwerenz A, Freyschlag C, Lohmeier A, Riemenschneider MJ, Thomé C, Brawanski A, Proescholdt MA (2018) Efficacy of D,L-methadone in the treatment of glioblastoma in vitro. CNS Oncol 7:CNS18
Oppermann H, Matusova M, Glasow A, Dietterle J, Baran-Schmidt R, Neumann K, Meixensberger J, Gaunitz F (2019) D,L-Methadone does not improve radio- and chemotherapy in glioblastoma in vitro. Cancer Chemother Pharmacol 83:1017–1024
Volkow ND, Blanco C (2021) The changing opioid crisis: development, challenges and opportunities. Mol Psychiatry 26:218–233
Hancocks S (2019) The opioid crisis in the USA. Br Dent J 226:815
Chambless LB, Kistka HM, Parker SL, Hassam-Malani L, McGirt MJ, Thompson RC (2015) The relative value of postoperative versus preoperative Karnofsky Performance Scale scores as a predictor of survival after surgical resection of glioblastoma multiforme. J Neurooncol 121:359–364
Cata JP, Zafereo M, Villarreal J, Unruh BD, Truong A, Truong DT, Feng L, Gottumukkala V (2015) Intraoperative opioids use for laryngeal squamous cell carcinoma surgery and recurrence: a retrospective study. J Clin Anesth 27:672–679
Cata JP, Keerty V, Keerty D, Feng L, Norman PH, Gottumukkala V, Mehran JR, Engle M (2014) A retrospective analysis of the effect of intraoperative opioid dose on cancer recurrence after non-small cell lung cancer resection. Cancer Med 3:900–908
Forget P, Vandenhende J, Berliere M, MacHiels JP, Nussbaum B, Legrand C, de Kock M (2010) Do intraoperative analgesics influence breast cancer recurrence after mastectomy? A retrospective analysis. Anesth Analg 110:1630–1635
Doornebal CW, Vrijland K, Hau CS, Coffelt SB, Ciampricotti M, Jonkers J, de Visser KE, Hollmann MW (2015) Morphine does not facilitate breast cancer progression in two preclinical mouse models for human invasive lobular and HER2⁺ breast cancer. Pain 156:1424–1432
Gottschalk A, Sharma S, Ford J, Durieux ME, Tiouririne M (2010) Review article: the role of the perioperative period in recurrence after cancer surgery. Anesth Analg 110:1636–1643
Horowitz M, Neeman E, Sharon E, Ben-Eliyahu S (2015) Exploiting the critical perioperative period to improve long-term cancer outcomes. Nat Rev Clin Oncol 12:213–226
Mathew B, Lennon FE, Siegler J et al (2011) The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg 112:558–567
Zhang YF, Xu QX, Liao LD, Xu XE, Wu JY, Wu ZY, Shen JH, Li EM, Xu LY (2015) Association of mu-opioid receptor expression with lymph node metastasis in esophageal squamous cell carcinoma. Dis Esophagus 28:196–203
Lu J, Liu Z, Zhao L, Tian H, Liu X, Yuan C (2013) In vivo and in vitro inhibition of human liver cancer progress by downregulation of the µ-opioid receptor and relevant mechanisms. Oncol Rep 30:1731–1738
Singleton PA, Mirzapoiazova T, Hasina R, Salgia R, Moss J (2014) Increased µ-opioid receptor expression in metastatic lung cancer. Br J Anaesth. https://doi.org/10.1093/BJA/AEU165
Singleton PA, Moss J, Karp DD, Atkins JT, Janku F (2015) The mu opioid receptor: A new target for cancer therapy? Cancer 121:2681–2688
Belltall A, Mazzinari G, Diaz-Cambronero O, Eroles P, Argente Navarro MP (2022) Antagonists of the Mu-Opioid Receptor in the Cancer Patient: Fact or Fiction? Curr Oncol Rep 24:1337–1349
Beilin B, Shavit Y, Hart J, Mordashov B, Cohn S, Notti I, Bessler H (1996) Effects of anesthesia based on large versus small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesth Analg 82:492–497
Plein LM, Rittner HL (2018) Opioids and the immune system – friend or foe. Br J Pharmacol 175:2717–2725
Gaspani L, Bianchi M, Limiroli E, Panerai AE, Sacerdote P (2002) The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats. J Neuroimmunol 129:18–24
Eisenstein TK (2019) The Role of Opioid Receptors in Immune System Function. https://doi.org/10.3389/FIMMU.2019.02904. Front Immunol
Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI (2006) Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 105:660–664
Sessler DI (2008) Does regional analgesia reduce the risk of cancer recurrence? A hypothesis. Eur J Cancer Prev 17:269–272
Snyder GL, Greenberg S (2010) Effect of anaesthetic technique and other perioperative factors on cancer recurrence. Br J Anaesth 105:106–115
Bovill JG (2010) Surgery for cancer: does anesthesia matter? Anesth Analg 110:1524–1526
Cata JP, Gottumukkala V, Sessler DI (2011) How regional analgesia might reduce postoperative cancer recurrence. Eur J Pain Suppl 5:345–355
Buggy DJ, Borgeat A, Cata J et al (2015) Consensus statement from the BJA Workshop on Cancer and Anaesthesia. Br J Anaesth 114:2–3
Sung CH, Tsuang FY, Shih CC, Chang JL, Liao MH, Yang YW, Lee TS, Cheng HL, Wu CY (2021) Scalp Block Is Associated With Improved Recurrence Profiles in Patients Undergoing Primary Glioma Resection Surgery. J Neurosurg Anesthesiol 33:239–246
Privorotskiy A, Bhavsar SP, Lang FF, Hu J, Cata JP (2020) Impact of anesthesia and analgesia techniques on glioblastoma progression. A narrative review. Neurooncol Adv. https://doi.org/10.1093/NOAJNL/VDAA123
Xu J, Xu P, Li Z, Xiao L, Yang Z (2013) The role of glycogen synthase kinase-3β in glioma cell apoptosis induced by remifentanil. Cell Mol Biol Lett 18:494–506
Friesen C, Hormann I, Roscher M, Fichtner I, Alt A, Hilger R, Debatin KM, Miltner E (2014) Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma. Cell Cycle 13:1560–1570
Ramirez MF, Gorur A, Cata JP (2021) Opioids and cancer prognosis: A summary of the clinical evidence. Neurosci Lett. https://doi.org/10.1016/J.NEULET.2021.135661

No competing interests reported.

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Intraoperative opioids and disease-free survival in glioblastoma multiforme

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