Dutch study

Amir H ​​Zamanipoor najafabadi, BSC , PIM B van der Meer, BSC , Florien W Boele, Phd , Martin JB Taphoorn, MD, PHD , Martin Klein, Phd , Saskia M Peerdeman, MD, PHD , Wouter R Van Farth, MD, Phd , Linda Dirven, Phd , Dutch Meningioma consortium

Summary

CONTEXT

Many patients with intracranial meningiomas have a quality of health related to health (QVLS) and neurocognitive functioning up to 4 years after the intervention .

OBJECTIVE

Evaluate the long -term morbidity load (≥5 years) of patients with meningioma.

Methods

In this multicenter transversal study, patients ≥5 years after intervention (including active surveillance by magnetic resonance imaging (MRI)) were included and evaluated for -la QVLS (short-form Health Survey 36 or SF-36 test),

- neurocognitive functioning (neuropsychological evaluation),

- anxiety and depression (Hospital Anxiety and Depression Scale),

-Productivity at work (Short Form-Health and Labor Questionnaire).

Multivariable regression analyzes and by propensity score were used to compare patients and witnesses, and the different treatment strategies have been corrected to take into account possible confusion factors. Clinically relevant differences have been reported.

RESULTS

During a median monitoring of 9 years after the intervention , patients with meningioma (n = 190) reported more limitations due to physical (difference of 12.5 points, p = 0.008) and emotional (13.3 points, p = 0.002) compared to witnesses.

Patients also had an increased risk of suffering from anxiety (report of opportunities or ODDS ratio [gold]: 2.6, 95 % CI: 1.2-5.7) and depression (gold: 3.7, 95 % CI: 1.3-10.5).

deficits were found in 43 % of patients.

Although postoperative complications, radiotherapy and resection have been associated with a degradation of verbal memory, attention and executive functions compared to patients who have undergone a single resection, the only clinically relevant association was that between resection and degradation of attention (-2.11, 95 % CI: -3.52 to -0.07).

Patients in working age had less often a paid job (48 %) than the Dutch population of working age (72 %) and reported more obstacles to work than witnesses.

CONCLUSION

In the long term, a large part of patients with meningioma have an alteration of QVLS, neurocognitive deficits and high levels of anxiety or depression. Patients treated with resection 1 have the best neurocognitive functioning.

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Abbreviations

• • EORTC QLQ-BN20

    European organizational questionnaire for research and treatment of cancer on quality of life specific to the brain

• • Hads

    Anxiety and hospital depression scale

• • QVLS

    Quality of health related to health

• • Maas

    Study on aging in Maastricht

• • Mcid

    Clinically important minimum differences

• • MRI

    Magnetic resonance imaging

• • GOLD

    Odds ratio or chances report

• • AND

    Standard deviation

• • SF-HLQ

    Health and labor questionnaire

• • SF-36

    Health survey 36

Meningiomas represent 37 % of all primary brain tumors. The morbidity of intracranial meningiomas is mainly due to the compression of the cerebral tissue and the head nerves, or to complications linked to treatment (for example, hemorrhage). The primary treatment of these tumors consists of surgery, accompanied in certain cases of first -line or adjuvant radiotherapy.

The 10 -year survival is 82 % for grade I meningiomas of the World Health Organization (WHO).

We could expect that after the decompression of the central nervous tissue, the symptoms be resolved and that the functioning returns to normal in the long term.

Historically, long -term survivors of meningioma (≥5 years after the intervention) who have experienced the diagnosis and treatment of meningioma have often been considered to be “cured”. However, we know, thanks to cancer populations, that the experience of living beyond the tumor and treatment leads to considerable physical, cognitive and psychological problems throughout life (for example, neurocognitive disabilities and disturbed social roles), which often differ from acute complications that patients know during diagnosis and treatment (for example, altered physical function due to pares.

Although it is known that surgery and radiotherapy can improve health related quality (QVLS) and cognitive function in the first year, recent studies have shown that up to a median of 4 years after intervention, patients with meningioma can still suffer from an alteration of QVLS and neurocognitive functioning, as well as an increase in anxiety and depression.

Although there is a lack of data on the long -term effects of meningioma and its processing on these results, studies on low -grade glioma suggest that certain deficiencies and certain deficits are only manifested 5 years after treatment . In addition, the impact on participation in the company in terms of productivity at work is currently unknown.

We therefore sought to assess the long-term morbidity load (≥5 years after their intervention, that is to say the last antitumoral treatment or the initiation of active surveillance by magnetic resonance imaging [MRI]) of patients with meningioma in terms of QVLS, anxiety and depression, neurocognitive operation and productivity at work. We also evaluated whether these results were affected by the type of treatment received. Better knowledge of long -term survival problems in patients with meningiomas will help manage patient expectations and design long -term care plans for meningiomas, adapted to the physical, psychological and social needs of patients.

Methods

Participants

In this multicenter transversal study, consecutive patients with meningioma were included if the end of primary antitumoral treatment was at least 5 years before recruitment , or in the event of active MRI surveillance, at least 5 years after the diagnosis.

Eligible patients had to be 18 years of age or over, with a MEningioma of Grade I or II of WHO confirmed histologically in the event of surgery and a clinically suspected meningioma by MRI in the event of radiotherapy or active monitoring by MRI.

The consecutive patients were recruited in the external clinics of neurosurgery, neurology and radio-oncology of 2 university hospitals and a large non-university university hospital between July 2016 and April 2019. All eligible patients were asked for this study via a letter signed by a member of their treatment team.

Patients were excluded if they had history of whole brain radiotherapy, if they had received a diagnosis of type II neurofibromatosis or any neurodegenerative disease, or if they did not control the Dutch language sufficiently.

The caregivers of patients with meningioma were included for the comparison of QVLS, anxiety and depression, and productivity at work . They were eligible to participate if they were the spouse, a family member or a close friend of the patient, if they were 18 or older and if they provided the majority of emotional or physical support to the patient, according to the latter's statements. It was not possible to include a natural caregiver for each patient, because some patients have not been able to identify a motivated natural caregiver to participate in the study.

Procedures

This transversal study was approved by the medical ethics committees of all the participating centers (NL54866.029.15), and the participants gave their consent informed before the study procedures. The two questionnaires and the neurocognitive evaluation were administered once the same day, at least 5 years after their last treatment of meningioma. Consequently, the duration of follow -up varies between the last treatment of meningioma and the time of participation in the study. Clinical information on the tumor and processing was obtained from medical records, while socio -demographic information on patients and witnesses were obtained by a structured interview at the start of the assessments.

Questionnaires

Patients have fulfilled questionnaires measuring QVLS, namely health survey 36 (SF-36) and the European organizational questionnaire for research and treatment of cancer, specific brain module (EORTC QLQ-BN20). In addition, patients have completed the hospital's anxiety and depression scale (HADS) and the health and labor questionnaire (SF-HLQ) measuring productivity at work. Informal caregivers have fulfilled the same questionnaires, with the exception of EORTC QLQ-BN20 (additional digital content 1).

Neuropsychological evaluation

A full battery of neuropsychological tests has been administered by nurses or qualified research assistants.

She understood:

- the auditory verbal learning test,

- the concept movement test,

- the memory comparison test,

- the fluidity test of categorical words,

- the substitution test of digital symbols

- The Stroop test on colorful words.

On the basis of these tests, the scores of the following neurocognitive domains were calculated: executive functioning, verbal memory, working memory, psychomotor functioning, speed of information processing and attention.

Statistical analysis

The SF-36 and the QLQ-BN20 EORTC scores were presented for each field or scale/point, respectively, ranging from 0 to 100, the highest scores representing a better QVLS (SF-36) or a larger symptomatology (QLQ-BN20). The total scores for anxiety and depression, measured by the HADS scale, range from 0 to 21 and have been classified into three categories: no anxiety or depression (scores: 0-7), limit (scores: 8-10) and severe (scores: 11-21).

Work productivity has been measured as having a paid job or not and having experienced difficulties at work on 6 items. Unslated SF-36, EORTC QLQ-BN20 raw scores and HADS for patients and witnesses (i.e. natural caregivers) are presented in bar graphs.

The data relating to QVLS (SF-36 only), anxiety and depression, as well as productivity at work have been compared between patients with meningioma and caregivers, after correction of known confusion factors (that is to say age, sex, level of education and comorbidity) using a multivariable regression analysis. As a sensitivity analysis, the QVLS data measured with the SF-36 were also compared between patients with meningioma and the normative data published using a test to a sample.

For data from the QLQ-BN20 EORTC, we carried out a test T to a sample to compare the data from meningiomas with the basic data (that is to say after surgery but before any other anti-tumor processing) of glioblastoma of the Avaglio trial. This comparison with the most common primary malignant brain tumor was made to put the QVLS specific to the disease in context . As clinically important minimum differences (MCID) were not known for the instruments used specifically in patients with brain tumors, we used the MCID previously established for other groups of patients. The MCID has been set at 10 points for the EORTC QLQ-BN20 EORTC scales. Likewise, we have set the DICM for the SF-36 areas also at 10 points, because the majority of the DICMs reported for the various areas were <10 points. For the scales of the mental and physical components of the SF-36, the MCIDs were set at 4.6 points and 3.0 points, respectively.

In addition, for the calculation of Z scores for each neurocognitive field, the standard and standard deviations (and) of a reference sample of the MAAS study (Maastricht AGING Study; Large longitudinal study on the psychological and biological determinants of cognitive aging) were used, paired in the group for age, sex and level of education. By domain, the differences between Z scores greater than -1.5 were considered clinically relevant. In addition, patients with meningioma and working age have been compared to the Netweet Dutch population of working age (source: Netherlands statistics) in order to compare the percentage of patients with paid employment.

The effects of surgery and radiotherapy have been compared for the SF-36 HRQOL areas and neurocognitive functioning for which patients obtained clinically relevant scores lower than those of witnesses, which limited the number of statistical tests carried out. The propensity score regression analysis was used to adjust potentially relevant confusion factors (for example, age, tumor size, location of the tumor and the grade of Simpson).

An analysis of non-responses was carried out to compare the important clinical and socio-demographic characteristics between patients with meningioma who participated and those who chose not to participate.

For all statistical tests, the SPSS 23 software (IBM, Armonk, New York) was used, and a P of less than 0.05 was considered statistically significant.

RESULTS

Demographic data

In total, 190 patients (women: n = 149, 78 %) were included with median follow-up since the intervention of 9 years (IQR: 7-12 years) . ( Table , Figure 1 ). The patients were an average of 63 years (standard deviation: 12). The tumors were located on the basis of the skull in 92 patients (48%), on brain convexity in 93 patients (49%), and on leaflets in the optic or intraventricular nerve in 5 patients (3%). The majority of meningiomas treated surgically were classified in the rank I of WHO (88%).

Surgery was the first choice of treatment in 168 (88%) patients, 63 of which suffered from a postoperative complication, such as deficits of the cranial nerves (n = 8) or a leak of cerebrospinal fluid (n = 8). A total of 26 (14%) were treated with adjuvant radiotherapy and 13 (7%) per re -expressed. Primary radiotherapy was limited to 10 (5%) patients with tumors from the base of the skull complicated on the anatomical level. In total, 12 patients (6 %) were only followed by active monitoring by MRI without any anti -Tusto treatment. In total, 129 caregivers of patients with meningioma participating in the study were included, as well as the data of 151 participants in the MAAS study.

The analysis of non-responents has shown that patients with participants and non-participating meningioma were similar on important socio-demographic and clinical characteristics, with the exception of age, non-participating patients being slightly older.

Quality of life related to health (QVLS)

After correction of confusion factors, patients had clinically relevant QVL scores lower than those of witnesses in 2 of the 8 areas of SF-36: role limitations due to physical health problems (corrected difference of 12.5 points, p = 0.008) and role limitations due to emotional health problems (13.3, p = 0.002). In addition, they obtained statistically significant, but not clinically relevant, lower scores for 2 additional areas and 1 component score: social functioning (7.4, p = 0.008), vitality (7.1, p = 0.016) and the mental component (3.8, p = 0.005). No difference was found for the other four areas and the score of the physical component (Figure 2).

In the sensitivity analysis comparing patients with normative data to confusion factors, patients have obtained clinically relevant lower scores for a domain and a component score: role limitations due to physical health problems (unresalized difference of 12.2, p <0.001) and physical component score (5.0, p <0.001). They obtained statistically significant, but not clinically relevant, lower scores in three other fields: physical functioning (5.4, p = 0.004), general health (7.2, p <0.001) and social functioning (5.6, p = 0.005).

By comparing patients with meningioma with patients with glioblastoma after surgical intervention but never received chemotherapy or radiotherapy, we found that patients with meningioma had statistically similar scores on 4/11 scales/items of EORTC QLQ-BN20, showing alteration of QVLS: QVLS: QVLS Visual disorder (difference: 2.5, p = 0.078), communication deficit (-1.8, p = 0.291), headache (2.8, p = 0.296) and hair loss (2.3, p = 0.101). The differences were not clinically relevant for these scales/points or for any other scale/point with the exception of future uncertainty, for which patients with glioblastoma reported more uncertainty (Figure 3 ).

Anxiety and depression

Patients suffered more frequently from limit (8 %, n = 15) and severe (14 %, n = 27) anxiety, compared to witnesses (limit: 6 %, n = 8; severe: 3 %, n = 4; overall p = 0.047, Figure 4). Patients also suffered more frequently from limit (9 %, n = 16) and severe (8 %, n = 15) depression, compared to witnesses (limit: 3 %, n = 4; severe: 2 %, n = 2; overall p = 0.099, Figure 4). Compared to witnesses, patients presented an increased risk of developing limit or severe anxiety (ratio of opportunities or odds ratio (gold): 2.6, 95 % CI: 1.2-5.7) and limit or severe depression (gold: 3.7, 95 % CI: 1.3-10.5) after correction of confusion factors.

Neurocognitive operation

In total, 43 %(n = 82) of patients suffered from a clinically relevant neurocognitive deficit in at least one of the six measured areas, most often in the fields of information processing speed (n = 51, 27 %) and attention (n = 44, 23 %) (see Figure 5 for all areas). In addition, 47 (25 %) patients suffered from clinically relevant disability in at least 2 areas, 32 (17 %) patients in 3 areas, 22 (12 %) patients in 4 areas, 20 (11 %) patients in 4 areas and 7 (4 %) patients in 6 areas.

Productivity at work

Of the 190 patients with meningioma, 123 (65%) were aged 18 to 67 and considered to be working age. At the time of the evaluation, 50 % (62/123) of patients with meningioma had a paid job, against 72 % for the net average of the Dutch working age (p <0.001). The reasons invoked for not having paid employment were being at home (15 % for women, 0 % for men) or poor health (24 % for men and women). Patients have more likely to report obstacles to work (46 %) than witnesses (17 %, p = 0.005). The following problems at work have been reported as sometimes to always occur (Figure 6 ): reduced concentration (74%), slower work rhythm (78%), feeling of isolation (22%), delay in work (67%), need someone to take care of their work (42%) and difficulty making decisions (59%).

Impact of surgery and radiotherapy on QVLS and neurocognition

Patients treated with first -line surgery or radiotherapy have not obtained significantly different results in terms of QVLS or neurocognitive operation compared to patients followed by active MRI. However, the comparison between surgery and radiotherapy as a first -line treatment has shown that patients treated with radiotherapy have obtained significantly less good results in terms of verbal memory (-0.99, 95% CI -1.78 to -0.20).

Similarly, patients receiving additional radiotherapy after surgery have obtained less good results in verbal memory (-0.45, 95 % CI -0.86 to -0.03) than patients treated only by surgery. Patients who have suffered from a complication during their first surgical intervention obtained less good results in terms of attention (-0.78, 95% CI -1.42 to -0.14) compared to patients without complications.

In particular, the need for a second resection for a residual tumor or a recurrence has led to worse scores in terms of executive operating (-0.92, CI95% -1.78 to -0.07), verbal memory (-0.66, CI95% -1.25 to -0.08) and attention (-2.11, CI95% -3.52 to -0.71) Compared to patients who only needed one resection. With the exception of attention in patients requiring a second resection, the differences were not clinically relevant.

DISCUSSION

Key results

Although most patients with meningiomas have a benign grade i tumor according to WHO, with life expectancy close to normal, and that they are often considered to be healed after intervention, our results clearly show that patients always suffer from a significant burden linked to the disease, even after median follow -up of 9 years. Many patients suffer from clinically relevant alteration of QVLS and neurocognitive functioning, higher levels of anxiety and depression, and lower productivity levels at work. The type of treatment also had an impact on the results; Patients who underwent a single resection had better neurocognitive functioning than those who have undergone surgical complications, were treated with radiotherapy (additional) or had to undergo a new resection.

Limitations

Due to the transversal observational design of this study, no conclusion can be drawn on a possible improvement or deterioration after treatment and results could suffer from confusion and bias.

In particular for the comparison between patients treated with first -line surgery or radiotherapy, a selection bias could affect the results, because radiotherapy is often reserved for older patients, suffering from comorbidities or with a complicated anatomical location of the tumor. To reduce the impact of confusion factors on our results, especially when analyzing the cohort, we have corrected our analyzes to take into account multiple confusion factors using a multivariable regression analysis and propensity scores. In addition, we have included a limited number of patients with active MRI surveillance or radiotherapy as the only treatment.

Although radiotherapy is supposed to have a negative impact on long -term results, the number of patients included with radiotherapy was too low to detect small significant differences. In addition, we may not take into account the specific quality of life problems for meningiomas, because we used the SF-36, widely used, which allows comparisons with other groups of patients.

There is no validated QVLS instrument specific to the meningiomas that we could have used. In addition, as there is no specific dicm for brain tumors for the questionnaires used, we have used more conservative DICMs based on other patient populations. Therefore, the results presented could be more conservative. Finally, we used both caregivers and normative data as controls for QVLS . As caregivers are indirectly affected by the evolution of the disease of their loved ones but do not suffer directly from the same physical and neurological consequences, we were able to assess more precisely the impact of the tumor and its treatment . The results of the two comparisons were quite similar, showing that compared to informal caregivers or normative data, patients obtained clinically relevant scores lower in several areas/components of SF-36.

Interpretation

Existing executives for survival issues describe that if, in the acute phase of diagnosis and treatment, we can expect bodily deficiencies, in the longer term, patients mainly experience disturbances in their social roles. Indeed, we have found that patients in the longer term have reported clinically relevant limitations of roles due to physical and emotional health problems, while previous studies have reported deficiencies in cognitive and physical functioning to a median of 6 months and 4 years after surgery. Remarkably, we found that patients with Benin meningioma after long -term follow -up had QVLS scores similar to those with naive glioblastoma and radiotherapy glioblastoma.

Although the 2 groups are not comparable in terms of follow -up after the start of treatment, patients with glioblastoma are often considered to have disabilities in terms of QVLS. To replace the results in the context of major surgery in conditions not linked to the SNC, which can also have a huge long-term impact on the functioning and well-being of patients, patients with meningioma reported a physical and mental QVLS lower than that of patients of the same age having undergone an aorto-coronary puncture, and a lower mental QVLS but more than patients undergoing a total hip prosthesis. No neuropsychological alteration was reported in patients with meningioma up to a median of 3 years after the intervention.

In patients with low -grade glioma, these deficits could only appear after more than 10 years of follow -up. Indeed, we found that neurocognitive deficits were present in more than 40% of patients with meningioma. The limited data published on anxiety and depression describe that around 10% to 15% of patients with meningioma suffer from severe depression or anxiety, before and 6 months after surgery. It seems that this percentage does not decrease over time because we have found percentages of patients at risk of depression or severe anxiety by 8% and 14%, respectively. In addition, we have found that patients have less often a paid job than the Dutch population paired by age, because they were identified as home people (female patients 15%, male patients 0%) or due to poor health (male and female patients: 24%).

Compared to patients with prolactinoma, another benign intracranial lesion mainly affecting women, patients with working age of working age had less often a remunerated job (patients with meningioma: 50%; patients with prolactinoma: 80%). Likewise, patients with breast cancer have no paid jobs due to their health problems and less often because they were at home. Although they were not measured over time, we found that patients treated with a single surgical intervention have reported better QVLS and better neurocognitive functioning compared to patients treated mainly by radiotherapy or additional radiotherapy or by resection. Anterior longitudinal studies on patients with meningioma have reported an improvement but not normalization of neurocognitive functioning and QVLS after surgery.

Patients treated with radiotherapy showed an improvement in QVLS in the first 6 months after irradiation, with deterioration to the levels before irradiation after 2 years. A single study (n = 18) compared the effects of postoperative radiotherapy in patients with meningioma, not reporting any difference in QVLS. However, monitoring limited to 1 year has prevented the evaluation of a possible long -term neurotoxicity of radiotherapy.

Generalizable results

We believe that our results can be generalized, because the number of missing data was very limited (all assessments were carried out on the same day), patients were recruited in university and non-university hospitals in the Netherlands, and because our analysis of non-response has shown that our study population was representative of the general population of meningiomas.

The generalization of the study to other countries could be hampered by the differences between health care environments and the impact of cultural differences on results such as quality of life.

CONCLUSION

Although the continuous improvement of surgical and radiotherapeutic techniques for the treatment of meningiomas has led to an increase in the number of long -term survivors, there were little things about the survival problems of these patients.

The results of this study show that the burden of long -term disease is considerable . This information is important to properly inform health care providers and patients over the long -term sequelae of the tumor and treatment. This makes it possible to properly manage expectations and develop care plans for long -term survivors, focusing on identified long -term disabilities.

Finally, the results of this study can be used as a reference for the comparison of multiple results centered on the long -term patient when evaluating new treatment methods. The possible determinants of the long -term morbidity load are an important subject and should be explored in more detail in future studies.

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