The impact of intraoperative use of opioids on the survival of individuals undergoing surgery for Glioblastoma

doi:10.21203/rs.3.rs-4620627/v1

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The impact of intraoperative use of opioids on the survival of individuals undergoing surgery for Glioblastoma

https://doi.org/10.21203/rs.3.rs-4620627/v1

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Introduction: Glioblastoma (GBM) is a primary tumor of the central nervous system (CNS). It is one of the most aggressive tumors affectinghumans, hasno cure, and has an extremely inverse prognosis, with an average survival ranging from 7 to 15 months. The role of opioids, either in stopping or stimulating tumor progression, has been demonstrated. The main objective of this study was to investigate the effect of intraoperative opioid use on patient survival.

Methods: This retrospective study included 133 patients who underwent 167 surgical procedures for glioblastoma resection. The inclusion and exclusion criteria were as follows: patients older than 18 years, of both sexes, and those with confirmed GBM. Patients who died in the postoperative period due to 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) scores, duration of the surgical procedure, opioid dose, overall survival, disease-free survival, sex, and race. Correlation tests were performed using the Spearman test, a T1-robust ANOVA test was used to assess variance between the opioid dosage groups, and Cox proportional hazard models were used to evaluate the association between opioid dosage and patient survival.

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 the total opioid dosage. There was no association between the total opioid dosage and the survival times of patients.

Conclusion: This study suggests that there is no relationship between intraoperative opioid dosage and overall ordisease-free survival in patients receiving glioblastoma treatment.

Glioblastoma

Opioids

Survival Analysis

Gliomas are the most common primary tumors of the central nervous system (CNS), with a frequency of approximately 48%. The annual incidence is approximately 6/100,000 individuals in the general population[1–3]. It originates from glial cells, astrocytes, and oligodendrocytes; thus, astrocytomas and oligodendrogliomas are present. These tumors were initially classified by the World Health Organization (WHO) according to their histological characteristics as 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), or Grade IV (glioblastoma (GBM)) regardless of the originating cell lineage. The histological differences that define each grade are as follows: Grade II, isolated cytological atypia; Grade III, anaplasia and mitotic activity; and Grade IV, microvascular proliferation and/or necrosis[3].

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

The most effective treatment for GBM is maximal surgical resection, followed by concomitant radiotherapy and chemotherapy, further, the diagnosis of GBM is can only be accomplished by histopathological analysis of the fragments [5].

The surgical procedure "per se" induces significant organic stress that negatively impacts the immune system. Moreover, other factors, such as pain, tumor tissue manipulation, corticosteroids, blood transfusions, and anesthetic and analgesic drugs, also act as immunosuppressants during the preoperative period, which may increase the risk of postoperative complications, such as infections[6].

Recently, some authors have investigated whether the opioid drug family, which is commonly used for pain control after extensive surgical procedures, can have an impact on the disease-free survival of patients receiving surgery for brain tumors, given the presence of opioid receptors in several tumor cells.

Opioids act through their receptors, among which, µ, k, and δ are prominent. The µ-opioid receptor (ROM) is present in the 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 literature, and studies have shown antagonistic effects depending on the type of opioid, dose, and route of administration[7–9].

Several studies have demonstrated the presence of ROM in tumor cells. An association between increased ROM expression in tumor cells and disease progression and spread has been demonstrated in malignant neoplasms of the esophagus, liver, lungs, and breast[10, 11]. There is also evidence of the presence of the opioid receptor µ in GBM cells[12, 13].

Several articles have analyzed the relationship between perioperative opioids and survival, both recurrence-free and overall, with inconclusive results. While some studies present an anti-tumoral role for opioids, other articles show that in some cases, opioids might present a pro-tumoral action[14].

Although some studies have already investigated the relationship between opioid usage and survival of patients after surgery for glioblastoma[15], no study has analyzed how the dose of intraoperative opioids might affect patient prognosis.

Therefore, the primary objective of this study was to investigate the correlation between intraoperative opioid dosage and disease-free survival, and the secondary objective was to investigate the correlation between opioid dose and overall survival of patients.

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 at 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 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 and those who did not have specific data on the drugs used in the preoperative period in their records were excluded.

Analyzed Variables

Disease-free survival (DFS) 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 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 Overall survival (OS) analysis, 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), Karonofsky Performance Score (KPS) [16] before and after surgery, duration of the surgical procedure, and intraoperative opioid dose (fentanyl, sufentanil, morphine, and remifentanil).

The doses of the different opioids were analyzed individually and converted into Fentanyl doses in the following proportions: 1 µg of fentanyl was equivalent to 0.1 µg of sufentanil, 1 µg of remifentanil or 66.6 µg of morphine. This approach was necessary to obtain statistically significant data, and fentanyl was chosen because it is used 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 to 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 between opioid doses and 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. Patients receiving doses from the minimum value to the 1st quartile were classified as low dose, those from the 1st to 3rd quartile as moderate dose, and those up to the 3rd quartile to the maximum dose as high dose.

To verify the existence of a correlation between quantitative variables, Spearman's test was applied. For categorical (qualitative) variables, the chi-square test and Cramer’s V test were used.

The Robust T1-ANOVA test was used to assess the variance of means between more than two groups, and the Cox proportional hazard test was used to compare survival (hazard ratios) between groups. To test the assumption of proportional hazards between groups, the Schoenfeld test was applied. The significance level adopted for all the tests was 5% (p ≤ 0.05).

This study included 133 patients (45 females; 33.8%) and 88 males (66.2%). In total, 167 surgical procedures were performed. Categorical variables related to the patient's condition included race, presence of epileptic seizures, headache, and neurological deficits at diagnosis. Postoperative progression 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%)

Most patients presented with initial neurological deficits (69.1%) rather than other common signs and symptoms of brain tumors, such as headaches (55.64%) and epileptic seizures (23.31%) (Table 1).

Regarding variables related to surgery, most patients had a clinical-neurological status maintained during the immediate postoperative period (52.7%) 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 (Table 1).

For 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, duration of surgery, and the total intraoperative opioid dose in fentanyl equivalents. OS and disease-free survival (DFS) were also analyzed as quantitative variables (Table 2).

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
Overall 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

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 for considering high dispersion (Table 2).

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 of 31–60 µg fentanyl/kg of weight. Only two patients received doses above 120 µg/kg (Fig. 1).

Spearman's test was used to verify the existence of a correlation between the opioid dose and other quantitative variables. The results showed a significant correlation only between 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 greater the opioid dose used (Table 3).

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

The results of the chi-square test for associations between categorical variables and opioid doses did not reveal any significant differences (p > 0.05). Moreover, when the Robust T1-ANOVA test was applied to assess the variance in the means between the Opioid Dose groups for both disease-free survival and overall survival, no significant difference was found (p > 0.05) (Fig. 2).

Finally, the Cox proportional hazard test was applied to assess the probability of both disease-free survival and overall survival between the different opioid dose groups. Both models adhered to the proportional hazards assumption of the Cox proportional model; further, no statistical difference was found between the opioid dose groups for neither disease-free survival (Table 4) or overall survival (Table 5).

Table 4

Results from the cox proportional hazards model. df: Degrees of Freedom.
Dependent: Surv(Disease-Free Survival, Recidive)		n	Hazard ratio (95% CI, p value)
Opioid Dosage Group	low	22 (23.4%)
	moderate	45 (47.9%)	1.15 (0.68–1.93, p = .611)
	high	27 (28.7%)	1.03 (0.58–1.82, p = .929)
n = 94, events = 94, Likelihood ratio test = 0.34 on 2 df(p = .844)

Table 5

– Results from the cox proportional hazards model. df: Degrees of Freedom.
Dependent: Surv(Overall Survival, Death)		n	Hazard ratio (95% CI, p value)
Opioid Dosage	low	33 (26.8%)	Reference
	moderate	64 (52.0%)	1.33 (0.86–2.06, p = .199)
	high	26 (21.1%)	0.96 (0.57–1.61, p = .867)
n = 123, events = 123, Likelihood ratio test = 2.67 on 2 df(p = .264)

This study provides additional insights into the relationship between opioids and cancer. This study is unprecedented in the literature analyzing the effect of intraoperative opioid dose on survival in patients with glioblastoma and suggests that there is no relationship between the dosage of intraoperative opioids and the survival outcomes of patients undergoing surgery for GBM.

Regarding gliomas and anesthetic techniques, Sung et al. addressed this topic in a retrospective study of 230 patients who underwent their first surgery for glioma and were divided into two groups: those who underwent a scalp block with local anesthetic after the induction of anesthesia and those who did not. The group treated with scalp blocks had longer disease-free survival than the group not treated with a block. Importantly, this study included patients with Grade II or III gliomas[17].

Several in vitro studies have reported apoptotic effects of opioids on glioma cells. Xu et al. (2013) concluded that the use of remifentanil induces apoptosis in glioma cells[18], and Friesen et al. (2014) reported that D-methadone, which acts as a µ-receptor agonist, inhibits the growth of GBM cells[19]. Additionally, Brawanski et al. (2018) showed that high doses of both d, l-methadone have apoptotic effects on glioblastoma cells and interact with temozolomide, the main chemotherapeutic agent used to treat GBM[12]. Altinoz et al. (2019) showed that the use of noscapine might improve the treatment outcomes of glioblastomas.

Furthermore, in a review of the literature and mechanisms of action of the meperidine synthetic opioid, Altinoz et al. (2022) speculated that using this drug concomitant with tamoxifen chemotherapy might lead to improvement in outcomes of patients receiving glioblastoma, due to the synergistic action of both drugs and their relation to P-glycoprotein and ceramides[20]. Finally, in a study investigating the relationship between methadone and temozolomide, Honc and Novotny (2023) showed that methadone might potentiate the cytotoxic effects of temozolomide by impairing some key metabolic pathways in glioblastoma cells, Calcium Homeostasis, and dysregulation of PARP proteins[21].

However, other authors have suggested that the use of opioids is not associated with improved outcomes after surgery for gliomas. Oppermann et al. (2019) reported that the use of D,L-methadone did not potentiate the effects of several antineoplastic strategies, such as radiotherapy or chemotherapy (temozolomide), and only presented a cytotoxic effect on glioblastoma cells at concentrations up to 10µM, which are above the reported toxic doses for humans[22]. Additionally, in a narrative review of the literature, Vatter et al. (2020) demonstrated that the use of methadone as an antineoplastic adjuvant therapy is not supported by the literature, with few and heterogeneous results and studies reporting beneficial results using a higher than toxic dose of methadone[23]. Moreover, Liu et al. (2024), in a study comparing inflammatory biomarkers, found that patients using a high dosage of opioids presented higher values of neutrophil-to-lymphocyte ratio and reduced values of lymphocyte to monocyte ratio, suggesting that higher doses of opioids might promote inflammatory and immunosuppressive status in patients[24]. Finally, in a comprehensive review of the influence of anesthetic and analgesic techniques on GBM progression, Privorotskiy et al. (2020) demonstrated that there are very few studies on the use of opioids as anti-neoplastic agents in GBM cases, and that those that exist are conflating, with the majority showing no specific benefit[15]. These results are in line with the findings of the present study, which did not perceive a decrease in the Hazard Ratio between the different doses of intraoperative opioids.

The present study is not without limitations, firstly the opioid dosage categories were based on the total dose received by patients in the present study not in a stablished criterion, therefore for other groups of patients the “low”, “moderate” and “high” groups might differ in amount of opioid dosage. Nonetheless, the authors used this criterion to investigate whether higher concentrations of opioid usage might affect the survival of patients. Other limitation present in the study, is that the survival models were performed without considering other covariates, such as age, gender, and others, analysis that will be carried on future studies.

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 .

Ethical Approval

This study was approved by the Ethics Committee under CAAE: 90795518.6.0000.5411. All patients provided informed consent for the use of their data in this study.

Funding

No funding was received for this study.

Availability of data and materials

No data are available online; however, upon reasonable request, the author can share the data.

Author contributions

Study conception: Romero, F.R. ; Fukushima, F.B. and Naufal, R.F.F. Data collection: Reyes, L.I.C.M.G.; Wolak, Mario Jr. , and de Carvalho, G.C. Data analisys: Naufal, R.F..F; Romero, F.R., and Pokorny, G. Manuscript writting: Naufal, R.F.F. Revision and approval: Naufal, R.F.F. and Romero, F.R.

Correspondent author

Gabriel Pokorny. Email: [email protected]

Conflict Of Interest: The authors reports no conflicts to disclose.

Data Access Statement: There is no data associated with this manuscript online

Funding: There was no funding for this research

Ethical Approval: The ethics committee approved the research.

Informed Consent: The patients consented in having their data collected for the present study

Author Contribution

Study conception: Romero, F.R and Naufal, R.F.F. Data collection: Reyes, L.I.C.M.G.; Wolak, Mario Jr. , and de Carvalho, G.C. Data analisys: Naufal, R.F..F; Romero, F.R., and Pokorny, G. Manuscript writting: Naufal, R.F.F. Revision and approval: Naufal, R.F.F. and Romero, F.R.

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No competing interests reported.

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The impact of intraoperative use of opioids on the survival of individuals undergoing surgery for Glioblastoma

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