Charles Champeaux-Deond ^{A, B} , Panayotis Constantinou ^C , Philippe Tuppin ^C , Matthieu Resche-Rigon ^B and Joconde Weller ^D

^A Department of Neurosurgery, Lariboisiere Hospital, Paris, France;

^B Inserm U1153, Statistic and Epidemiologic Research Center Sorbonne Paris Cité (Cress), Eccsrra Team, Universitite de Paris, Paris, France;

^C French National Health Insurance (CNAM), Paris, France;

^D REGIONAL AGENCY OF SANTE, SAINT DENIS, FRANCE

 

SUMMARY

Context : survival after meningiomas surgery is often reported without taking into account other causes of death.

Methods : We have processed the national health data system, the French administrative medical database to recover the cases of meningomes processed surgically. The Relative Survival Method (RS) of Pohar allows has been implemented.

Results : a total of 28,778 patients was identified between 2007 and 2017, 75% of which are women .

• The median age at the time of surgery was 59 years.
• The cranial convexity was the most frequent location (24.7%) and,
• Blessed meningiomas represented 91.5% of all meningiomas.

Median follow-up was 3.5 years (interquartile interval: 3.4-3.5).

At the time of data collection, 2,232 patients died.

The five -year survival compared to the expected survival of a French standard population paired for age and sex was 96.2%; Confidence interval (CI) of _95% [95,7-96,8].

The excess of absolute risk of death by Méningioma was 973/100,000 people-years IC _95% [887-1068] (p <0.001).

The standardized ratio of corresponding mortality was 1.8 _95% [1.7-1.9] (p <0.001).

In the adjusted model,

• Male sex (Hazard Ratio [HR] ¼1.39, _95% CI [1.27-1.54], p <.001),
• Age at the time of surgery (hr¼0.97, _95% CI [0.97-0.97], p <.001),
• Type 2 neurofibromatosis (HR¼2. 95, _95% CI [1.95-4.46], p <.001),
• Comorbidities HR¼1.39, _95% CI [1.36-1.42], p <.001),
• Location (hr¼0.8, _95% CI [0.67-0.95], p¼.0111),
• Preoperative embolization, (hr¼1.3, _95% CI [1. 08-1.56], part.00507),
• Derivation of cerebrospinal fluid, (hr¼2.48, _95% CI [2.04-3.01], p <.001),
• Atypical histology (hr¼1.3, _95% CI [1.09-1.54], p¼.00307) or malignant (hr¼1.86, _95% CI [1. 56-2.22], p <.001),
• Surgical recovery (HR¼1.19, _95% CI [1.04-1,36], p¼ .0122)
• and radiotherapy (hr¼1.43, _95% CI [1,26-1,62], p <.001)

were established as independent predictors of RS.

Conclusion : This unique study highlights mortality associated with meningiomas. Many factors such as sex, age, location, histopathological classification, surgical recovery influence the RS.

KEYWORDS

Meningioma; relative survival; result ; health care database; predictors

 

Introduction

Considered as meningothelial cells of the arachnoid , meningiomas are the most frequent primary extra-cranial tumors, representing 36.8 % at 37.6 % in the central Brain Tumor regisry of the United States. ¹ Most meningiomas are sporadic and their surgical incidence is around 5/100,000 people per year in France. ^2.3 Ionizing radiation, hormonal treatments and certain genetic diseases such as type 2 neurofibromatosis are identified risk factors. ^4.5

The 2016 classification of the World Health Organization (WHO) of tumors affecting the central nervous system (SNC) recognizes three grades of meningiomas.6 Mesningiomas of Grade I of WHO, or mild, are the most common and generally have a good evolution. ^2.3.7 Grade III or maline meningiomas are rare and aggressive neoplasms whose prognosis is bad. ⁸ The behavior and evolution of the atypical MEMBS of Grade II of the WHO is intermediate. ⁹

Treatment options include regular monitoring, in particular for accidental meningiomas, symptom control, surgical excision, irradiation (RTO]) and, occasionally, chemotherapy, but maximum adapted resection is generally the treatment of choice. Most meningiomas evolve indolent after resection, but some have aggressive behavior which is not solely linked to a high histopathological grade. Only a fraction of patients who have been made with meningioma will die due to the refractory evolution of their disease . In addition, the majority of patients with meningiomas are women over the age of 50 who may have additional comorbidities and an altered health.

Global survival (OS) generally underestimates the real survival rate, especially in the elderly who can die from other causes. The study of survival after meningioma surgery must therefore take this fact.

 

Objective

The objective of this study was to estimate relative survival (RS) after meningioma surgery and, to search for associated factors using the French health insurance database.

Methods

Clinical equipment

We carried out a national, descriptive, observational and retrospective analytical retrospective study from the national health data system (SNDS), the French national medico-administrative database. Méningiomes incidents never operated were not considered in this study ; Only surgically treated tumors have been taken into account.

We used an algorithm combining two variables to obtain the appropriate cases:

• The type of surgical procedure carried out identified by the common classification of French medical acts (CCAM) and,
• The primary diagnosis according to the international classification of diseases (CIM-10) as described above.^2,4,10,11

The 40 CCAM codes describing the resection of extracerebral intracranial tumors have been classified into eight anatomical locations according to their insertion into the Dural database. Blessed meningiomas have been considered corresponding to the CIM- 10 D32 codes, atypical to D42 and, clever at C70. We defined the first recorded date of meningioma surgery as the index date. Patients under the age of 18 have been excluded (N¼118). The progression was defined as any new treatment for a recurrence of meningioma, for example a new surgery, RT or stereotaxic radiosurgery. The predictive death -related morbidity index (MRMI) of mortality of all causes was used to assess the seriousness of the overall health statement^12.

Statistical methods

For the description of the cohort, the continuous variables are presented in the form of medians and interquartile intervals (IQR); The categorical variables are presented in the form of frequencies and proportions. The survival was measured from the first date of meningioma surgery until the date of death or censorship in the last follow -up. ¹³ Essentially, there is no lost patient in the SNDS since those who died are automatically recorded as such in the database. In addition, due to the structure and functioning of the SNDS, there is no missing data in any of the variables evaluated in this study. To take into account the lack of survival specific to a cause, we have carried out an analysis of the survival of patients with meningiomas compared to the expected survival in the general French population appeared according to age and sex. The RS is therefore calculated as the SG observed in the cohort of meningiomas compared to that expected in the general French population. We used the POHAR method, a new non -parametric estimator and without a clear survival, even in the presence of informative censorship. ^14-16 All tests were bilateral and statistical significance was defined with an alpha level of 0.05 (p <0.05). The analyzes were carried out using the SAS Enterprise Guide (version 7.15 HF8, SAS Institute Inc., Cary, NC, USA) and the programming language and the R software environment for statistical calculation and graphics (R version 4.1.2 (2021-11-01) ¹⁷ .

Compliance with ethical standards

This study was conducted according to ethical directives for epidemiological research in accordance with the ethical standards of the Helsinki Declaration (2008), with the National Commission for Data Protection (CNIL), an independent national ethics committee, authorization number: 2008538; According to record directives for studies carried out from health data collected routine and, according to SAMPL directives. ^18.19 The informed consent was not required due to the retrospective nature of the study and, the use of anonymized data, in accordance with the European General Data Protection Regulations (RGPD UE 2016/679).

 

Table 1. Characteristics of the 28,778 patients.

Characteristics n or median % or iqra

Female sex 21 593 75 %

Median age at the time of operation 59 years IQR [49-68]

Age at the time of the operation

-<50 years 8397 29.2%

-> 50 years -<59 years 7252 25.2%

-> 60 years -<69 years 7327 25.5%

-> 70 years 5802 20.2%

Neurofibromatosis (NF2) 165 0.6 %

Cyproterone acetate 1240 4.3 %

Mortality-related morbidity index (MRMI) B 0 IQR [0-2]

-0 (ref.) 12,663 51.2 %

-1                                                                                                          4810                                     19,5%

-2                                                                                                          2011                                     8,1%

-3                                                                                                          2974                                     12%

->4                                                                                                       2270                                     9,2%

Location

-Cranial convenience 7106 24.7%

-Anterior skull 3888 13.5 %

-Aveide skull 6132 21.3%

-posterior skull base 3484 12.1 %

-Falx cerebri or parasagittal 5157 17.9%

-Intraventricular 206 0.7%

-Colonne Vertebral 2805 9.7%

Pre-operative embolization 1355 4.7%

Invasion of the venous sinus 3299 11.5%

Neuronavigation 10221 35.5%

Reconstruction of the dura-mother 6299 21.9%

Cranioplasty 1775 6.2 %.

BURNING OF THE LCR 556 1.9%

Classification of the tumor

–Benign 26.319 91.5%

–Atypical 1726 6%

–Malignant 733 2.5%

Surgical resumption for recurrence 2170 7.5 %

Radiation therapy 2621 9.1%

Stereotaxic radiochurgery 909 3.2 %

^A IQR: Interquartile interval.

^B Calculated indices using exclusively weights related to the condition.

 

Image 1. Graphic representation of global (OS) and relative (RS) survival of meningiomas.

 

Results

Population description

We identified 28,778 patients who were made with a meningioma between 2007 and 2017. Sixty-five percent were women and, the median age during the first meningiom surgery was 59 years, IQR [49-68]. According to the MRMI index, men presented significantly more comorbidities than women (p <0.001). The cranial convexity was the most frequent location (24.7%), followed by the base of the average skull (21.3%) (sphenoid wing). Spinal tumors represented 9.7 %. Blessed meningiomas represented 91.5%, atypical 6% and clever 2.5% (Table 1). Median follow-up was 3.5 years IQR [3,4-3.5].

Table 2. Univariable relative survival (RS) after meningioma surgery.

Invariable

Variable RS ^A [95 %CI] ^b Value P

Sex

-Homme 93.5% 92.1-94.9

-Femme 97.2% 96.7-97.7 <.001

Age at the time of the operation

-<50 years 97.6% 97.1-98.1

-> 50 years -<59 years 97.6% 96.9-98.2

-> 60 years -<69 years 95.0% 94.0-96.0

-> 70 years 94.1% 92.1-96.1 <.001

Neurofibromatosis (NF2)

-Absent 96.3% 95.8-96.8

-Present 89.0 % 82.8-95.7 .00273

Cyproterone

-Absent 96.2% 95.7-96.8

-Present 96.6 % 94.6-98.7 .097

Mortality -related morbidity index (MRMI)

-0 (ref) 101.2 % 100.8-101.6

-1                                                                                          98.3%                   97.2-99.5

-2                                                                                         95.6%                   93.3-98.0

-3                                                                                         87.4%                   85.1-89.7

->4                                                                                      73.8%                   70.6-77.0            <.001

-Cranial converse (ref) 96.8% 95.8-97.8

-Anterior skull 95.7% 94.3-97.0

-average skull base 96.5 % 95.5-97.5

-posterior skull base 95.8% 94.5-97.1

-Parasagittal 94.5% 92.7-96.3

-Falx cerebri 93.6% 91.4-95.7

-Intraventricular 89.5% 83.0-96.5

-Colonne vertebral 100.5% 98.5-102.5 <.001

Preoperative embolization

-Absent 96.4% 95.9-97.0

-Present 92.7% 90.3-95.1 .00288

Invasion of the venous sinus

-Absent 96.4% 95.9-97.0

-Present 95.0% 93.4-96.6 .0126

Reconstruction of the Duree Mother

-Absent 96.4 % 95.8-97.0

-Present 95.9% 94.8-96.9 .466

Cranioplasty

-Absent 96.4% 95.9-97.0

-Present 93.8% 91.8-95.8 .00309

Shunt LCR

-Absent 96.7% 96.1-97.2

-Present 76.9% 72.0-82.1 <.001

Classification of the tumor

-Balit 97.0 % 96.5-97.6

-Atypic 93.9 % 91.7-96.2

-Malign 73.0% 67.9-78.4 <.001

Surgical resumption for recurrence

-No 97.0 % 96.5-97.6

-Yes 90.6% 88.8-92.4 <.001

Radiotherapy

-No 97.5% 97.0-98.1

-Yes 87.0% 85.1-88.9 <.001

Stereotaxic radiochurgery

-No 96.2% 95.7-96.7

-Yes 97.7% 95.7-99.8 .376

Note: the values ​​P displayed in bold have reached statistical meaning.

^has risk report.

^b 95 %trust interval.

 

Result

At the time of data collection, 2,232 patients died. The median age at the time of death was 73.2 years , IQR [63.9-80.9].

In total, 179 patients (0.63 %) died in the first postoperative month, 303 (1.06 %) within three postoperative months and 570 in the year (1.98 %).

The five-year survival was 90.7% , 95% confidence interval (IC) [90.2-91,1] (image1 (a)). The five-year survival compared to the expected survival of a standard French population paired for age and gender was 96.2%, 95% IC [95.7-96.8], which suggests that meningioma contributed to overall mortality (image 1 (b)). The excess of absolute risk of death linked to meningiomas was 973/100,000 people-years, IC95% [887-1068] (p <0.001). The value P of the log-trip test between the survival curves observed (n¼2232) and expected (n¼1239) was highly significant (p <0.001). The associated standardized mortality ratio was 1.8 CI95 % [1.7-1.9] (p <0.001).

Predictors of relative survival

Most of the variables studied have reached statistical significance and have been associated with RS in univariable analyzes (Table 2). In the adjusted model, male sex (HR ¼ 1.39, 95%CI [1.27-1.54], p <.001), age at the time of surgery (HR ¼ 0.97, 95%CI [0.97-0.97], p <.001), neurofibromatosis type 2 (HR ¼ 2.95, 95% [1.95-4. [1.08-1.56], p¼. 1.86, 95%CI [1.56-2. RS (Table 3).

Table 3. Multiplicative regression model for relative survival (RS) after meningioma surgery

Multivariable

HRA variable [95 %CI] ^b Value P

Sex (ref.: Woman)

-Homme 1.39 1.27, 1.54 <0.001

Age at the time of (continuous) 0.97 0.97, 0.97 <, 001

Neurofibromatose (NF2) (Ref .: No)

-NF2 2.95 1.95, 4.46 <, 001

Morbidity index linked to mortality (MRMI) (continuous) 1.39 1.36, 1.42 <.001

Location (ref.: Cranial convexity)

-Anterior skull 1.26 1.08, 1.47 .00409

-ADE SKATED SHOULD 1.22 1.05, 1.4 .00853

-posterior skull base 1.27 1.08, 1.5 .00457

-Falx cerebri 1.01 0.85, 1.2 .891

-Intraventricular 1.76 1.11, 2.81 .0165

-Colonne Vertebral 0.8 0.67, 0.95 .0111

Preoperative embolization (ref .: no)

-Yes 1.3 1.08, 1.56 .00507

Shunt LCR (Ref.: No)

-Yes 2.48 2.04, 3.01 <0.001

Classification of the tumor (ref .: Benigne)

-Atypic 1.3 1.09, 1.54 .00307

-Malign 1.86 1.56, 2.22 <.001

REPOSION FOR RESPIDIVE (Ref.: No)

-Yes 1.19 1.04, 1.36 .0122

Radiotherapy (Ref.: No)

-Yes 1.43 1.26, 1.62 <0.001

Note: the values ​​P displayed in bold have reached statistical meaning.

^a danger ratio.

^b 95 %trust interval.

^C calculated according to the method of Andersen et al.

 

 

Discussion

Key results

In the standard survival analysis, subjects are supposed to know only one type of event, generally a recurrence or a death. In reality, several types of events can occur. In these cases, other events - called competing events (EC) - may prevent the occurrence of the event of interest or modify the risk that the primary evaluation criterion occurs.

The traditional methods of survival analysis, such as the Kaplan-Meier method and the proportional risk model of Cox, are not designed to take into account the competing nature of multiple events, because they assume the absence of competitor risk (RC). Net survival describes the probability of surviving a diagnosis of tumor in the absence of competing causes of death. It is defined as the survival that could be obtained if all the risks of dying other causes than the disease in question, here meningioma, were eliminated. Net survival is now a major epidemiological indicator, estimated routine for many neoplasms, either by specific survival (CSS) or by RS. The first requires knowing the cause of death. However, when the causes of death are unavailable or unreliable, net survival can be evaluated by the RS, which uses the mortality of all causes of the group studied and the “expected” mortality of a group without disease with the same demographic characteristics. ²⁰

As such, this work represents a unique and modern analysis, based on the population, of the mortality of patients with meningioma. Taken out of an unreadmitted sample, this RS study after meningioma surgery and its predictors using the national database, fills a gap so far existing in the literature. Analysis of the RS presented here indicates that meningioma is a component of the cause of mortality in the population concerned.

Boundaries

The SNDS strengths reside both in the high number of patients and in the exhaustiveness of the data available in all hospitals in France. The representativeness of the database is almost perfect, since it includes the entire population of the country, or 68 million inhabitants, which constitutes one of the largest BDMA in the world. ²¹ Compiled from a number of institutions, its precision is limited by irregularities in the collection and registration of data. Despite certain limits, the SNDS is a precious tool to assess the future of meningiomas. It offers an incomparable way to explore associations with other pathologies, drugs or combined surgical treatments that could not be evaluated before. The retrospective nature of this study, as well as the lack of clarity concerning the reasons for treatment and non -homogeneous management strategies without random assignment, must be taken into account when evaluating the results.

Table 4. Revue to the literature of studies on relative survival (RS) of meningiomas.

See link

 

Interpretation

Only a handful of studies reported the Rs of the Méningiomes.

In a 1989 Norwegian study, Helseth et al. were the first to describe an RS rate of five years (RSR) of 84% for 1438 patients under the age of 60 . ²² Kallio et al. and SANKILA et al. From the neighboring country, Finland, found Rs at five years of 86.9%, 95%CI [84-89] and 88%, respectively. ^23.24 more, Sankila et al. noted that the RSR of patients increased significantly during the period studied between the first (1953-1968) and the second (1968-1978) period.24

This was confirmed by Brodbelt et al. Who observed that the results after meningioma surgery improved during the period examined. ²⁵ This increase of approximately 10% of the RSR in the past 30 years is consistent with the progress made in the surgical techniques of meningioma , anesthesiology, regardless of the increase in life expectancy (Table 3).

Unsurprisingly, in addition to a temporal influence, Sant et al. also found a spatial variation in the RS of meningiomas, with an average rate at five years of 88.7%, ranging from 79.5% in Eastern Europe to 93.4% in Northern Europe. ²⁶ The comparison between the few available studies is however somewhat uncertain due to the different statistical methods used. Nevertheless, the cohort based on the population we have described here is similar to previous studies with a predominant proportion of women between 70 and 75% and an average age at the time of surgery ranging from 50 to 63 years (Table 3). However, the RSR at five years of 96.2%, 95%CI [95.7-96.8] that we present in this modern series, is the highest reported.

Image 2. Comparisons of relative survival curves.

Prognostic factors

Melingiomas linked to meningiomas have been shown to , including sex and age have been found in most studies, including ours (Table 4). ^24.25,27

Unsurprisingly, the RS after meningiomas surgery is better in young adults and, in women.

On the contrary, for Sankila et al., Long -term mortality was associated with young and male patients: in the age group less than 45 years, the relative risk was 3.8 times higher for men than for women; No difference in this type was found in the highest age group. 25 for Brodbelt et al. There was a significant reduction in net survival at five years beyond the age of 69, less than 83 % in men and 87 % in women. 25 in patients aged 54, the RS at 10 years was 95 % against 90 % in older patients (p <0.001) in the study by Holleczek et al.27 in the Dolececk et al. Similar for age groups up to around 55, when survival was gradually becoming less favorable with age advancement.²⁸

Better results for women have already been described for many tumors and are assigned to less comorbidities and/or better clinical performance. ²⁹ Our results confirm this assertion, men having significantly more comorbidities than women (p <0.001). A point of MRMI has significantly decreased RSR. This effect was even more marked in patients with a high level of comorbidities, with an RSR of only 73.8 %, CI95 % [70.6-77.0] for patients with an MRMI of 4 or more (Image 2 (F)).

NF2 patients are predisposed to develop SNC lesions, including intracranial and spinal meningomes which are often multiple and develop at a young age. ³⁰ In our study, NF2 patients presented significant excess mortality with a median age on the death of 40 years, IQR [29-47]. Similar findings have been made by Otsuka et al. Who conclude that the long -term survival rates of NF2 patients have proven to be unfavorable, especially for those whose symptoms began before the age of 25. ^4.31

An advantage of the SNDS which uses the CCAM classification is its ability to provide a precise location of the dual insertion of meningioma . The majority of meningiomas are generally located in intracranial (90%) and, convexity is the most frequent location in a quarter (24.7%) . The RSR is better for convex meningiomas (96.8%, 95%CI [95.8-97.8]) and lower for intraventricular (89.5%, 95%CI meningiomas [83.0-96.5]).

Nine seven seven percent of meningiomas were removed from the spine, against 4.4% for Dolecek et al. and 7.7% for Brodbelt et al. Who say that patients with spinal meningiomas are better out in all grades, sexes and ages. ^25.28 We agree with this assertion by founding that spinal meningioma is not a condition threatening life and that its withdrawal does not alter survival.

The histopathological classification has often been shown to be one of the strongest factors in survival. As for Holleczek et al, patients with mild meningiomas had an rs at five years of 97% and therefore a minor excess mortality linked to meningiomas. Considering only mild meningiomas, based on an analysis of 205 patients between 1985 and 2003, they found a RSR at five years of 92%, which is slightly lower than the rate observed here. ³² The RSR at five years for patients with atypical meningomes stretched from 80% to 96%, which demonstrates the significant increase in mortality linked to the tumor along the increase in the grade of WHO. ²⁷ With regard to malignant meningiomas, RSRs extended from 30% to 73.0% in our study. ²⁷ For Porter et al, the Five Year's RS from malignant meningiomas was 67.3 %, CI95 % [58,674.6] and 88.7 %, CI95 % [87,190,1] for non -clever meningiomas. ³³ RS at five years for mild meningiomas, meningiomas at the limit of malignancy and malignant meningiomas were 85.6 %, 82.3 %and 66.0 %, respectively, in the study by Dolececk et al. ²⁸ In the latest CBTRUS report, the RSR at five for non-maline meningiomas (2004-2015) was 88.0 %, CI95 % [87.8-88.3] and 67.7 %, CI95 % [66.2-69.3] for Maline meningiomas (2001-2015). ¹ The classification of meningiomas has often been controversial, in particular for the grades II and III whose definition has changed with the updates of the classification of the WHO. This may partly explain the observed variations in RSR. Obviously, the behavior of meningiomas cannot be explained by the only histological characteristics, as expressed by Dolececk et al. Who found that for mild cases, the RS at five was significantly more favorable for women than for men, blacks than whites, Hispanics than non-Hispanics, spinal meningiomas than the other locations of the primary site ²⁸ .

Despite generally indolent biological behavior, the result of patients treated for meningioma can sometimes be bad and, in this study, those who needed reoperation or RT have a reduced RS of 90.6%, 95%CI [88.8-92.4], 87.0%and 95%CI [85.1-88.9], respectively.

Conclusion

This unique study highlights the mortality associated with meningiomas, including many factors such as sex, age, location, histopathological classification, surgical recovery or RT necessary for aggressive tumors, influence RS.

Thanks

Marjorie Boussac and Julius Kemme of the CNAM for their help in extracting data; Hugo Varet, bioinformatics and biostatistic hub, Department of Informatique Biology, Institut Pasteur, Paris, France; Jean-Philippe Jais, University of Paris Descartes-University H^Opital Necker-Children Malades, Paris, France; Ms. Segolene Van Outheusden, London, England, United Kingdom, for her rereading of the manuscript, her correction of English, her verification of grammar and spelling.

Ethical approval

This study was conducted according to ethical directives for epidemiological research in accordance with the ethical standards of the Helsinki Declaration (2008), with the National Commission for Data Protection (CNIL), an independent national ethics committee, authorization number: 2008538; According to record directives for studies carried out from health data collected in a routine manner and, according to the SAMPL directives. 18,19 informed consent was not required due to the retrospective nature of the study and the use of anonymized data, in accordance with the general European data protection regulations (RGPD EU 2016/679).

Declaration of disclosure

No conflict of potential interest has been reported by the authors (s).

Funding

No funding was received for this research.

Orcid

Charles Champeaux-De buys http://orcid.org/0000-0002-0356-0893 6 C. Champeaux-Depond et al.

Data availability declaration

Restricted, the authors do not have permission to share the data.

Code availability

On request.

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