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December 26, 2022

German study: quality of life related to health and clinical results after radiotherapy of patients with intracranial meningioma

Quality of life related to health and clinical results after radiation therapy of patients with intracranial meningioma

By Dominik Lisowski, Jannik Trömel, Paul Lutyj, Victor Lewitzki, Philipp E. Hartrampf, Bülent Polat, Michael Flentje & Jörg Tamihardja

Summary

This retrospective study, conducted in a single establishment, focused on long -term result, toxicity and quality of life related to health (QVLS) in patients with meningioma after radiotherapy.

We have analyzed the data of 119 patients who received radiotherapy in our service between 1997 and 2014 for an intracranial meningiom of I-III of the WHO. Fractional stereotaxic radiotherapy (FSRT), intensity modulation radiotherapy (IMRT) or radiosurgical radiation have been applied.

The questionnaires EORTC QLQ-C30 and QLQ-BN20 were filled for the evaluation of the QVLS. The overall survival (OS) for the entire study group was 89.6 % at 5 years and 75.9 % at 10 years. Local control (CL) at 5 and 10 years old was 82.4% and 73.4%, respectively. A local recurrence was observed in 22 patients (18.5 %). Acute and chronic toxicities of highest grade were observed in seven patients (5.9%) and five patients (4.2%), respectively. The overall state of health was evaluated with an average of 59.9 points (SD 22.3) on the QLQ-C30. In conclusion, radiotherapy has made it possible to obtain very good long -term survival rates and the control of the tumor with low levels of severe toxicities but with a deterioration of the long -term QVLS.

Meningiomas are neoplasms derived from the arachnoid cells of leptumenincs and are the most frequent primary intracranial tumors in adults with 15 to 30 % (1). Women are twice more often affected as men, however, men tend to develop more aggressive forms of meningiomas (2). Meningiomas are classified into three groups by the World Health Organization (WHO) according to their histological characteristics.

About 80 to 85 % of all meningiomas are classified in the category of non -maline meningomes (Grade I of WHO), which generally have a slow growth rate and non -invasive expansion. Only 5 to 15 % of meningiomas are considered to be atypical meningiomas (Grade II of WHO) and only 1 to 3 % are malignant meningiomas (Grade III of WHO) with a trend in brain invasion (3.4).

A new classification of meningiomas is based on molecular markers to predict clinical results with more precision (5). Multimodal treatment of meningiomas depends on the classification of WHO as well as the state of resection and may include surgery, radiotherapy, therapy by peptide -receiving (PRRT) or vigilant expectations (6).

Radiation therapy is generally applied as adjuvant treatment or in the event of a relapse . In the event of unbeatable meningioma, primary radiotherapy is the most common therapeutic option. It can be conducted in terms of intensity modulation radiotherapy (IMRT), fractional stereotaxic radiotherapy (FSRT) or radiosurgery (7). Although modern irradiation techniques have decreased the quantity and severity of acute and late toxicity, previous publications have observed high -level undesirable effects after brain radiotherapy, visual field deficit, neuropathy, brain necrosis, pituitary dysfunction and vascular brain events (8,9,10,11,12,13).

Cognitive disorders, memory loss and personality changes can be objectively difficult to quantify , but have a huge impact on the daily life of individuals (9,14). Consequently, any acute or late side effect can lead to a significant deterioration in the quality of health related to health (QVLS) (15). Until now, little data has been published on toxicity and QVLS after radiotherapy in patients with meningioma. Consequently, this monocentric retrospective analysis aimed to provide data on QVLS, side effects and long -term efficiency after radiotherapy in a large group of meningioma patients.

Methods

We have retrospectively analyzed the data of 119 consecutive patients with meningiomal who were processed in our service between 1997 and 2014 . The ethical approval was lifted by the local ethics committee of the University of Wuerzburg due to the retrospective nature of the study and all the procedures carried out were part of the routine care. All methods were carried out in accordance with the ethical standards of the establishment's research committee and the 1964 Helsinki Declaration and its subsequent amendments or comparable ethical standards.

The informed consent was obtained from all the subjects and/or their legal tutor (s) before planning of treatment. The main evaluation criterion of our study was the quality of life, evaluated by the main questionnaire on the quality of life of the European organization for the research and treatment of cancer (EORTC) (QLQ-C30) version 3.0 and the questionnaire of the module on the brain cancer of the EORTC (QLQ-BN20).

The secondary evaluation criteria were toxicity linked to treatment, local control (CL) at 5 and 10 years and overall survival (SG). Local control was defined as the time elapsed between the start of the irradiation and the appearance of the first progression on the site treated with imaging. Overall survival has been defined as time elapsed between diagnosis and the last documented follow -up or death, whatever the cause. We have been included all patients with meningioma who were treated with radiotherapy during the given period and who had no sign of spinal infiltration. In the event of multiple treatment series, we have analyzed a single series.

Patients with history of another cancer, regardless of the previous processing, were included in the database. All cases were discussed in an interdisciplinary neuro-oncological revision committee before treatment.

Treatment planning

For normofractional radiotherapy, the raw tumor volume (GTV) has been extended from 8 to 15 mm, depending on the WHO grade and the location of the tumor, to generate the clinical target volume (CTV). The CTV was extended by 3 mm to obtain the Target Planning Volume (PTV). The dose was prescribed at the average Dose of the PTV. In case of stereotaxic radiotherapy, a margin of 1 to 2 mm was added to the GTV for the PTV. The IMRT was administered according to the STEP-AND-SHOOT technique with 3 to 9 fields or according to the VMAT technique (Volumetric Intensity Modulated Arc Therapy) with two dynamic arcs. All radiotherapies were made with photon bundles using a linear Elekta Synergy® or Siemens Primus accelerator. The GTV has been delimited on computer assisted tomography (TAO) with magnetic resonance imaging (MRI) coinciding with Pinnacle (3) (Philips Radiation Oncology Systems, Fitchburg, Wi, USA).

Follow up

Clinical and radiological follow -up including an MRI with contrast was carried out 6 to 12 weeks after radiotherapy, then once or twice a year, unless an earlier examination is envisaged due to a suspicion of relapse. Imaging examinations were evaluated by two (neuro) independent radiologists. The dimensions of the tumor have been measured from an axial MRI sequence weighted in T1 with contrast or a scanner with contrast. In the event of a multifocal presence, the location of the tumor was defined by the site of the largest lesion. The RANO criteria (Responses Assessment in Neuro-ONCOLOGY) were used to assess the progression of the tumor (16). The location of the tumor was classified in the base of the skull, the cerebral falx, the hemispherical convexity or the sheath of the optic nerve.

The clinical examination included the evaluation of the neurological state. For the assessment of acute and late toxicity, version 5.0 of Common Terminology Criteria for opposing events (CTCAE) has been used. Acute toxicity was evaluated up to 90 days after the end of the irradiation. For the evaluation of the quality of life, the questionnaires EORTC QLQ-C30 version 3.0 and EORTC QLQ-BN20 were filled during follow-up visits or sent to patients. The Karnofsky Performance Status (KPS) was evaluated before the treatment and at the time of the QVLS assessment. The data from the QLQ-C30 and QLQ-BN20 have been compared to the already published data of historic cohorts (17,18,19,20,22,23).

Statistics

All data was analyzed with IBM SPSS Statistics 26.0. The statistical significance threshold has been set at a bilateral P <0.05. We assumed that the data of the study carried out were missing at random (Mar). As very few values were missing, we used the suppression in pairs to maintain a sufficient sample size and power. With regard to questionnaires QLQ-C30 and BN20, a relevant clinical difference was defined when the point difference was greater than 10 points (24.25). The SG and the LC were calculated using Kaplan-Meier statistics. The Log-Rank test was used to determine the statistical significance of the difference in SG or CL between the different groups. For multivariate analysis, a regression of proportional risk of COX has been carried out. Mann-Whitney-U and Kruskal-Wallis tests were carried out due to parameters not normally distributed according to the Shapiro-Wilk test. To correlate the grades of toxicity with the characteristics of the treatment, the location of the tumor and the QVLS data, the meaning of the Kendall Tau-B correlation coefficient has been evaluated. Multiple linear regressions have been used to find confusion factors for overall health.

Results

Treatment results

Meningioma was histologically determined in 76 patients (63.9%). In 43 patients (36.1%), the diagnosis was based on radiological signs after examination by magnetic resonance imaging (MRI) by at least two (neuro) radiologists. Irradiation was administered in 56 patients (47.0 %) during the initial diagnosis, 41 patients (34.5 %) having been irradiated in the year following the diagnosis. The other 63 patients (52.9%) were treated at the time of the relapse of meningioma. In total, 37 patients received primary radiotherapy due to the non-development of meningioma or inoperability that was conditioned by age and comorbidities. The median age of patients who received primary, adjuvant and recurrent radiotherapy was 70.2, 58.4 and 56.7 years, respectively. The median axial size of the tumor was 2.5 cm (IQR 1.5-3.8 cm) in the longest orientation at the start of radiotherapy. FSRT, IMRT and radiosurgery alone were carried out in 67 (56.3 %), 48 (40.3 %) and four (3.3 %) patients, respectively. Sequential extra irradiation was administered in 38 patients (31.9 %). A total median dose of 54.0 Gy (IQR 54.0-58.5 Gy), 60.0 Gy (IQR 54-61.2 Gy) and 60.0 Gy (IQR 59.4-60.3 Gy) was administered for the MEMB MES MS I, II and III, respectively. For stereotaxic radiotherapy, a total median dose of 19.5 Gy (interval 17.5-21 Gy) was prescribed at the 68 % PTV encompassing the isodosis. A patient was treated by an entire brain irradiation at 30.0 Gy and a sequential boost on the lesion of meningioma at 15.0 Gy. In 26 patients (21.8 %), Imaging by post-emission (TEP) to (68) Ga-Dota0-Phe1-Tyr3 Octreotide (Dotatoc), at (68) OCTREOTATE (Dotatate) or (18) F-Fluoroethyl-L-Tyrosine (FET) was carried out and merged to improve the definition of the target volume. Nine patients (7.6 %) received an additional RTPE using (177) Lu-Dotatoc with an average dose of 7.5 Gy (standard deviation ± 0.3). Three patients received concomitant or sequential chemotherapy. The characteristics of all patients are summarized in Table 1.

Table 1 Characteristics of patients (n = 119).

Full table

Quality of life

As 37 patients (31.1 %) had already died at the time of the survey, 82 questionnaires were sent or sent, 49 of which were duly completed and returned, which gives a response rate of 59.8 %. A questionnaire was returned with the notification that the corresponding patient had died. The median KPS of the patients interviewed before radiotherapy and at the time of the QVLS evaluation was 90 respectively (interval 50-100) and 90 (interval 40-100). The median kps of the entire study group was 80 (fork 30-100). The questionnaires were filled in the median 4.8 years (IQR 2.7-9.2 years) after radiation therapy by patients of 64.4 years (IQR 59.0-72.5 years). Of the 49 responders, three received additional cranial radiotherapy and four sequential extracranial radiotherapy. Analysis of the basic characteristics of patients between the group of responders and that of non-repairrs was not significant, except for the PRRT (additional table S1).

In terms of self-assessment, the overall state of health was evaluated with an average of 59.9 points (SD 22.3) on the EORTC QLQ-C30 with functional scales ranging from an average of 55.6 to 71.2 points (Table 2). We were able to detect a relevant decrease on the functional scale for physical functioning, the role, cognitive and social functioning, which was accompanied by an increase on the scale of symptoms for fatigue, pain, dyspnea, insomnia, constipation and financial impact. There was no statistically significant correlation between the maximum grade of chronic toxicity and fatigue (p = 0.41), nausea and vomiting (p = 0.43), pain (p = 0.12), dyspnea (p = 0.5), insomnia (p = 0.35), loss of appetite (p = 0.20) 0.09), diarrhea (p = 0.49) and financial difficulties (p = 0.46). Sequential radiotherapy, secondary metachron, meningiomal secondary tumors were not confusion factors for overall health on QLQ-C30 (p ≥ 0.05). On the QLQ-BN20 EORTC, the most frequent disabilities were drowsiness, uncertainty about the future and weakness of the legs (Table 2). Compared to previous cohorts, our data showed partially less good results on the QLQ-C30 (Figure 1) and on the QLQ-BN20 (additional figure S1).

Table 2 Scores of the ITEMS du EORTC QLQ-C30 and BN20 (n = 49).

Full table

Table 1

(a) Comparison of the functional scales of the QLQ-C30 with the data published above. Higher scores in functional areas suggest a higher level of operation and better quality of life. Ql2 = global state of health (revised); PF2 = physical functioning (revised); RF2 = functioning of roles (revised); EF = emotional functioning; See = Cognitive operation; SF = social functioning. (b) Comparison of QLQ-C30 symptom scales with previously published data. Higher scores in the symptomatic fields suggest a lower level of operation and a worse quality of life. Abbreviations: FA = Fatigue; Nv = nausea and vomiting; Pa = pain; Dy = dyspnea; SL = insomnia; AP = loss of appetite; Co = constipation; Di = diarrhea; Fi = financial difficulties. *Unpublished data.

Side effects

Acute toxicities linked to radiation and having clinical significance (CTCAE grade ≥ 3) were recorded in seven patients (5.9 %) . It was in particular a case of amaurosis with prior alteration of visibility and three cases of dizziness.

The other toxicities of Grade CTCAE 3 were as follows: nausea, headache, irradiation dermatitis, fatigue and mucosite. In two cases, the irradiation had to be interrupted due to a deterioration of the general state. Acute side effects of grade 1 and 2 occurred in 52.9% and 37.8% of cases, respectively. Fatigue, alopecia, headache, radical dermatitis, dizziness, as well as nausea and vomiting were the most frequently reported acute side effects. In 3.4 % of cases, no adverse effects have been reported.

Severe chronic toxicities (CTCAE grade ≥ 3) were observed in five patients (4.2 %). There was a case of overditas (grade CTCAE 4) and a case of amaurosis (grade CTCAE 4) with an insufficiency of the anterior pituitary gland (grade CTCAE 3). The other three cases suffered from fatigue, exhaustion, confusion or headache (all of grade ctcae 3). Chronic CTCAE 1 and 2 chronic side effects were observed in 11.8 % and 20.2 % of patients, respectively. The most frequent chronic side effect was chronic headache, which occurred in 7.5 % of cases. In addition, a circumscribed toxicity of the SNC (6.7 %), memory and concentration disorders (5.9 %) as well as fatigue (5.8 %) were relatively frequent.

All average dose values for risk organs in our study group were lower than the recommended limits. Patients with grade toxicities ≤ 2 received an average total dose of 54.9 Gy. The average total dose in patients with grade toxicities ≥ 3 was 57.9 gy. There was no statistically significant correlation between the maximum toxicity grade and the total dose (p = 0.55), PTV (p = 0.86) GTV (p = 0.52) or the location of the tumor (p = 0.56). There was a statistically significant correlation between the grade of toxicity of acute fatigue and the scope of QLQ-C30 fatigue symptoms (p = 0.03).

Local control

Median follow-up was 5.4 years (IQR 2.9-9.7 years). The estimated rates of CL at 5 and 10 years were 82.4 % and 73.4 %, respectively (fig. 2A). The median time until recurrence was not reached at the time of data analysis. In total, 22 patients (18.5 %) had a relapse in the field, three patients with MEMB MESGI MENINGIOME, SIX MENINGIOMA OF GRADE II of WHO and eight MENINGIOMA OF GRADE III of WHO. A relapse also occurred in five patients without meningioma confirmed histologically. A patient with highly suspected type II neurofibromatosis was diagnosed with a relapse of meningioma twice. The histological grade was significant and suggestive to influence the LC in the univariate (p <0.001) and multivariate (p = 0.05) analysis, respectively (fig. 2b). The rank of Simpson (i-iii vs. iv-v) had no statistically significant impact on the cl. The location of the tumor (p = 0.032) as well as the GTV for the patient's subgroup with OMS II and III grade meningiomas (p = 0.023) were significant in univariate analysis, but not in multivariate analysis. No significant difference of CL could be observed by comparing a cumulative dose of ≥ 60 Gy versus <60 Gy for all patients (p = 0.37) or for patients with MEMBS II and III grade meningiomas (p = 0.46).

Table 2

Local control shown by Kaplan-Meier analysis for all patients (A) and laminate according to the WHO ranking (B). The WHO classification was suggestive to influence local control (p = 0.05). Global survival is represented by an analysis of Kaplan-Meier for all patients (C) and laminate according to the WHO classification (D). The WHO classification was highly significant for global survival (p = 0.002).

Global survival

In total, 38 patients died at the time of the investigation. Of the 38 deaths, 16 patients (42.1%) were presumed deceased from meningioma disease and ten patients (26.3%) succumbed to comorbidities . In 12 cases (31.6 %), the cause of death was not clear. The SG estimated at 5 and 10 years was 89.6 % and 75.9 %, respectively (fig. 2C). The median SG was 17.5 years. Survival rates differ significantly according to the WHO grade (p = 0.002). KPS (≥ 90 % vs. <90 %) (p = 0.046), GTV (p = 0.001), the moment of radiation (p = 0.005) and age (p = 0.001) had a significant impact on the SG in univariate analysis. After a multivariate analysis, the OMS grade (p = 0.002) and the GTV (p = 0.001) remained significant for the SG (fig. 2D). The SG was not significantly affected by sex, the grade of Simpsons, the location of the tumor and the tumor volume before treatment. As for the CL, no significant difference in the SG was found by comparing radiotherapies with a dose climbing greater than 60 Gy for all patients (p = 0.32) or for patients with OMS II and III grade meningiomas (p = 0.08).

Discussion

To our knowledge, this study is the first to assess HRQOL data using QLQ-C30 and BN20 questionnaires for patients exclusively with meningioma and having received radiotherapy. Our research in the database has only found a few publications evaluating QVLS using QLQ-C30 and BN20 questionnaires in meningioma patients, most of them in the form of non-planned subgroup analysis (17,18,19,23). The response rate for QDV evaluation was 59.8 %. We could not detect a specific reason for the missing return of the 32 questionnaires and we can only speculate on the reason why the response rate was limited. Although we could not find any significant difference between the groups who responded and not having responded, except for the PRRT (additional table S1), a selection bias cannot be excluded due to the limited response rate. Our data shows slightly lower QVLS results compared to data already published for patients with meningioma, although comparability can be limited due to the different methods of acquiring data and the composition of patient groups (26). For example, Erhart et al. carried out a preselection of patients by excluding patients with severe cognitive disorders, which gave rise to higher QVLS scores (23). Shin et al. provided no additional information on the composition of the groups of patients with meningioma (19). Budrukkar et al. Assessed the QVLS in a subgroup of patients with benign brain tumors, which was not limited only to patients with meningiomas (18). Konglund et al. brought back higher QLQ-C30 scores, which is probably attributable to group differences because their cohort was made up of 94% benign meningiomas resulted without radiotherapy (17). Primary radiotherapy is often chosen for advanced and inoperable tumors and mild meningiomas should not be irradiated after a complete resection according to the directives of the European Neuro-Oncology Association (EANO) (27,28).

The heterogeneity of our examination group examined must be taken into account. Our study group was mainly composed of patients with unfavorable tumor location and 100 patients received radiotherapy as first -line treatment or at the time of relapse. Recurrent or incompletely resonated meningiomas are likely to have less good results, with more clinically significant side effects and, therefore, a lower QVLS (13). The grade II (16.8 %) and III (15.1 %) meningioma rate of the WHO in our study was higher than the average, which leads to the over -representation of high grade meningiomas (Grade II and III of WHO). In addition, 21 patients (17.6 %) of our study group reported another malignant tumor before the QDV assessment, which could be a factor of confusion.

The QDV was determined within a median period of 4.8 years after treatment in our study, which leaves the possibility that other diseases negatively influencing QDV be confusion factors, such as a stroke or cognitive deterioration due to aging. The absence of longitudinal evaluation of the QVLS is a limiting factor in our analysis, because the QVLS data were only evaluated at a precise moment in monitoring. There is therefore a lack of an investigation prior to treatment to compare the QVLS and identify possible confusion factors or patient subgroups with higher QVLS deterioration. Given that only long -term QVLS was evaluated in our study, the beneficial effects directly after radiotherapy or surgery resulting in functional gains and better QVLS have not been measured, unlike the studies of Budrukkar et al, Konglund et al and Bitterlich et al. (17,18,29).

The severe acute toxicities evaluated by doctors only appeared in 5.9% of cases , confirming that radiotherapy has light side effects when applied in patients with meningioma. The only case of acute lovers could be linked to the growth of the tumor, because the patient suffered from a serious visual impairment before radiotherapy and received palliative radiation to a lower dose. Although 36.2 % of patients reported chronic toxicities, only 4.2 % suffered from a chronic side effect of CTCAE grade ≥ 3. Our results comply with data previously published in terms of acute and late toxicities (0-49.9 %) (7,10,12,14,30.31).

Our median dose of applied radiation was comparable to that of existing literature. Based on the data already published, a dose of 54-60 GY is indicated and well tolerated for the MEMB MES MOS. In our Cohort of Méningiomes de Grade I de l'OMS, a dose up to 66.0 Gy was accepted if histopathological specimens had angiomatous or fibrous components. For high grade meningiomas, a total median dose of 60.0 Gy was prescribed in our study. A minimum dose of 60 Gy is generally prescribed for MENINGIOMS OF GRADE III of WHO to ensure long -term local control (32.33). The prescription of the dose for the MENINGIOMS of Grade II of the WHO, however, is not consistent in the literature. Depending on the state of resection, high -dose irradiation of 60 Gy or 70 Gy has been prescribed for all patients with Grade II meningiomas in the EORTC 22042 study, while patients with grade II meningiomas of WHO newly diagnosed with total macroscopic resection of 54 gy in the RTOG 053934.35 study. Survival without progression (SSP) and the SG at three years were comparable in both studies. The long -term results of the two studies have not yet been published. In retrospective analyzes, the increase in dose is however associated with an improvement in the clinical result and can be prescribed for the MEM Grade II meningiomas (32,33,36,37).

The existing reports on the factors influencing the SG and the CL for meningiomas are inconsistent, except for the rank of the WHO (11,15,30,38,39,40,41). In accordance with these results, our data confirmed that the rank of WHO had a significant impact on the SG in univariate and multivariate analysis and also affected local control. Due to the lack of studies with a large number of patients, statistics for the SG and CL in the MENINGIOMS of Grade II and III of the WHO show a wide variance (0.0-89.0%) (additional table S2) (30,32,33,38,40,42,43). Our CL estimated at 5 years for MENINGIOMS of Grade II of WHO (66.7%) and Grade III of WHO (53.1%) is compatible with the majority of published data (additional Table S2) (11,13,15,30,32,33,38,40,42,45,47). Our survival rates at 5 years and 10 years for each OMS grade, however, seem more favorable than those published. This could be due to the fact that our low number of patients with high -risk meningiomas limits statistical information. In addition, the histological classification of older samples has not been updated according to the revised classification system of WHO since 2016, which has influenced the indication of radiotherapy, the target volume, the applied dose and probably the result (48). Although the concordance for the histopathological classification of meningiomas is relatively high, there are still divergences between observers and between institutions, which could cause a bias in the results (49).

Conclusion

In our cohort of patients with meningiomas, mostly at an advanced or relapse stage, radiotherapy has shown an excellent prognosis with regard to SG and LC and an acceptable QVLS with low toxicity reported by doctors. The deterioration of the QDV must be considered in relation to the risk of recurrence of meningioma and can therefore guide decision -making in favor of or not radiotherapy. Prospective studies should aim to improve QVLS without deteriorating the oncological result.

Data availability

The data sets generated and/or analyzed during this study are available from the corresponding author on reasonable request.

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