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Women’s Risk of Meningioma Recurrence: The Experiences of a Survivor Support Group

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Abstract
Introduction: Asking female survivors from a meningioma support group about their experiences and disseminating the results can inform future patients about possible outcomes, strengthen bonds within the patient community and help others understand the impact of meningioma diagnosis and therapy.

Materials and Methods: Survivors were recruited from the support group, Meningioma Mommas, to complete an online survey. The respondents (N=139) provided complete information on their initial diagnosis and recurrence; the majority (N=110) received surgery or radiation. Characteristics of those who received treatment (N=110) were examined at survey completion and at initial diagnosis. Risk of recurrence was shown by year since initial diagnosis and examined using Cox proportional hazard models (median follow-up 2.75 years).

Results: The median age at diagnosis was 38 years. Among those treated, approximately 23 percent experienced a recurrence within five years of initial diagnosis and 42 percent experienced a recurrence within 10 years. No significant differences in recurrence risk were found by race/ethnicity, meningioma grade, treatment type or pregnancy history; however, older women (> 38 years) had a higher risk of recurrence (hazard ratio 2.85; 95% CI 1.10-7.38) than younger women (< 37 years). 

Discussion: This study found that members of a meningioma support group who were older at diagnosis experienced a higher risk of recurrence. The results demonstrate the feasibility of using social media to survey patient support group members, which suggests great potential for future studies within meningioma and beyond. Although the results may not be generalizable widely, the findings have direct relevance for the group members.


Abbreviations used in this paper:
MMS = Meningioma Momma Survey; NSFG = National Survey of Family Growth; WHO = World Health Organization; GTR = gross total resection; STR = subtotal resection


 

meningioma

Introduction
Meningiomas are the most common primary brain tumor, with a prevalence rate of 97.5 in 100,000 U.S. adults, overall (12,63,64). Although often asymptomatic, they can cause debilitating symptoms such as seizures, muscle weakness, hearing problems, loss of vision, and even death (7,12,21). The majority of meningiomas are benign (World Health Organization [WHO] grade I); nonetheless, at least 20 percent are atypical (WHO grade II), and one to two percent are malignant (WHO grade III) (8,21,67). Some people choose active surveillance if their meningioma is benign and asymptomatic; however, surgical removal (resection) is often the first line of treatment for meningiomas that are symptomatic, atypical or malignant. Radiation therapy is often used in lieu of, or in addition to, surgery when the meningioma cannot be completely resected due to size or location within the central nervous system (25). Chemotherapy is seldom used to treat meningioma and is typically only used for aggressive tumors that are not responsive to resection or radiation (3, 38, 58).

Multiple studies, both retrospective and prospective, have examined multiple risk factors for developing a meningioma (i.e., incidence), including biological markers (5, 26); smoking
(6,22); alcohol (6,23); cell phones (17,39); family history (14,63); body mass index (6,15); handedness (33); pregnancy (4, 34, 39, 68); hormones (4, 9, 36, 61, 68); breast cancer (19, 36,46,56); immune conditions (14,64); and head trauma (37,52). Many proposed risk factors have not been found to be correlated with meningioma formation; conversely, a few studies have identified a weak association between hormone replacement therapy (11,22,53,57); parity (53); family history (14,63); breast cancer (19,36,46,56); body mass index (6,15); and biological markers (5,26). The two predominantly accepted risk factors are neurofibromatosis type 2 (NF2; a genetic disorder) (2,41,54,62,63) and excessive exposure to ionizing radiation (e.g., X-rays and radiotherapy) (1,2,13,35,63). However, a recent meta-analysis by Xu and colleagues (65) found no conclusive evidence that X-rays increase incidence.

In addition to incidence, multiple studies have also examined the risks of meningioma recurrence; although, no such study has focused on women of childbearing age or members belonging to a meningioma support group. The recurrence rates reported in the literature are disparate, possibly due to variations in the patient follow-up period (e.g., 3, 5, or 10 years) and inclusion criteria (e.g., tumor grade and form(s) of treatment). However, two factors are most commonly shown to influence recurrence rates — tumor grade and treatment type — although tumor size has also been indicated in some studies (55). Anaplastic, or malignant meningiomas (WHO grade III), have the highest rate of recurrence, followed by those that are atypical (WHO grade II), with benign tumors (WHO grade I) having the lowest rate of recurrence (28,45,66). Additionally, meningiomas that undergo gross total resection (GTR; Simpson grade I or II) often have a significantly lower risk of recurrence as compared to subtotal resection (STR; Simpson grades III-V) (27,29,31,50,55).

A challenge in conducting studies to estimate meningioma recurrence rates is finding a large enough sample of involved meningioma survivors. For this reason, the majority of existing studies on patients with meningioma are retrospective medical chart reviews with records dating back several years. Although the results are generally valid, they typically represent only the outcomes at one particular hospital/clinic or geographical area. Patients may want results that are relevant to themselves. They want to know, “What about the experiences of patients like me?” and often turn to the Internet to conduct their own research and learn about the experiences of others through support groups like Meningioma Mommas.

Meningioma Mommas was founded as a 501(c)(3) not-for-profit organization in 2003 by Liz Holzemer, who describes the organization as “an alternative to the grim statistics, numbers, and percentages all-too-prevalent on the Internet” (43). The results of this study reflect the burden experienced by the members of the support group. Its focus on “mommas” originated from an initial aim to examine birth desires and intentions among female survivors (reference omitted for anonymity).

Social media provides a way to recruit respondents who are hard-to-reach due to geographical distance, disease rareness or unique perspective (e.g., patient vs. caregiver). Some examples of respondent diseases have included: xeroderma (30), congenital heart disease (32), lupus (24), hysterectomy (20) and vestibulodynia (16), and some perspectives have come from parents (32), siblings (40) or children (47). This is the first study to conduct a survey of female meningioma survivors through social media.

Materials and Methods

Participants
In this patient-centered study, we used social media to survey women from a meningioma online support group to examine potential risk factors for recurrence, including: race, age, menopausal status at time of diagnosis, pregnancy history and diagnosis and treatment information. Respondents were recruited to participate in an online survey through the Meningioma Mommas organization, a 501(c)(3) not-for-profit online support group founded in 2003 (43). Its mission is to provide “support and valuable resources to all those affected by meningioma brain tumors.” The organization is dedicated to raising meningioma awareness and funds for meningioma specific research.

Participants were recruited using two sampling methods: 1) a banner advertisement posted on the Meningioma Mommas website that, once clicked on, provided immediate access to the survey and 2) a direct email invitation sent by the organization’s founder to Meningioma Mommas members, which included a link to the survey.

Upon consent, each participant completed a screener to ensure that she met the inclusion criteria: aged 18 years or older, current U.S. resident and currently or previously diagnosed with a meningioma. Respondents were not compensated for participation and were able to withdraw from the survey at any time by closing their browsers. Data were collected from Sept. 20, 2013, to Jan. 16, 2014, and all procedures were approved by the University of South Florida Institutional Review Board.

Meningioma Mommas Survey Instrument
The Meningioma Mommas Survey (MMS) instrument was composed of six sections: screener (consent form); meningioma diagnosis and treatment; pregnancy and children; birth desires and intensions; risk of meningioma recurrence; and health, household, and survey experience. Each question required an answer in order to proceed through the survey. The survey took approximately 15 minutes to complete, and the last question included an open-text box for general comments. Screenshots of the survey instrument are available online (reference omitted for anonymity).

Each respondent was asked the following questions pertaining to initial meningioma diagnosis: 1) the date of diagnosis (month/year); 2) the grade at diagnosis (low [most common]/intermediate [atypical, clear cell, choroid]/high [malignant, papillary, rhabdoid, anaplastic]/not sure); 3) menopausal status at diagnosis; and 4) pregnancy status at diagnosis.

Each respondent was also asked about the treatment(s) associated with the initial diagnosis: 1) if surgery was performed in connection with the diagnosis and, if yes, when (month/year); 2) if radiation therapy was performed in connection with the diagnosis and, if yes, when (month/year) and what type (conventional/external beam/proton/brachytherapy/implants/CyberKinfe®/stereotactic/not sure); and 3) if medication was prescribed in connection with the diagnosis (list; check all that apply). If the respondent reported a recurrence, the same series of diagnostic and treatment questions regarding the second diagnosis were asked. Lastly, respondents were asked about their pregnancy history up to the day of survey completion.

Statistical Analysis
Recurrence analysis was performed using Kaplan-Meier curves and compared by age using a log-rank test. Univariate and multivariate analysis was performed using Cox regression. All descriptive and statistical analyses were performed in Stata/MP 13.1. A significance level of 0.05 was used to determine statistical significance.

Results
Of the 162 participants who provided consent for study participation, 146 completed the screener, 139 provided complete information on their initial diagnosis and recurrence (if any), and 110 reported having received surgery, radiation or both at initial diagnosis. Respondents who did not report any treatment also did not report any recurrence or progression. Among the 110 respondents who reported either surgery or radiation, the majority were white and non-Hispanic (95%), married (77%), working at a job or business (59%), previously pregnant (81%) and had an education beyond high school at time of survey (83%; Table 1). Median time since initial diagnosis (i.e., follow time) was two years and nine months.  

 

Peer Review Table 1 At time of initial diagnosis (Table 2), median age was 38 years and the majority of respondents (86%) were pre-menopausal. More than half (67%) of the respondents reported being diagnosed with a “low-grade” tumor (benign; WHO grade I), less than 10 percent reported being diagnosed with an “intermediate-grade” tumor (atypical; WHO grade II), and no one reported being diagnosed with a “high-grade” tumor (malignant; WHO grade III); nearly a quarter (24%) of the sample selected “Not sure, don’t know.”

 

Peer Review Table 2 At survey completion, 21 respondents reported one or more recurrences within the maximum follow-up period of 10 years (interquartile range 1.42 to 5.92 years). The follow-up was truncated at 10 years due to the paucity of respondents, with more than 10-years follow-up (N=10). Overall, the likelihood of recurrence was 23 percent at five years and 42 percent at 10 years (Figure 1). Among the 21 recurrences, three respondents were pregnant between initial diagnosis and recurrence, and each ended in a live birth. Each pregnancy began after initial diagnosis and ended prior to recurrence (specifically: 2, 4 and 6 months prior). Among the 89 non-recurrences, 17 respondents were pregnant at least once between initial diagnosis and time of survey, and 13 of these respondents had one or more live births (11 with one birth; and two with two births). All pregnancies started after diagnosis and ended at least two-months prior to survey. In other words, the 110 respondents were pregnant for at least 196 months after initial diagnosis combined, and zero had a recurrence while pregnant. Although the absence of any events prohibits the estimation of a non-zero likelihood (i.e., zero-cell), this evidence suggests that the 95 percent confidence interval for monthly likelihood of recurrence (i.e., hazard rate) while pregnant is between 0 and 1.5 percent (3/196; Rule of three), which is similar to the overall monthly likelihood of recurrence (0.64%; 21/3312; 95% CI 0.36%-0.90%).  

 

Peer Review Fig 1   The annual likelihood of recurrence is 4.23 percent (21/497; 95% CI 2.46%-5.99%). Based on the univariate analysis (Table 3), none of the respondent characteristics at initial diagnosis were significantly associated with recurrence at a p-value less than 0.05. Based on the multivariate analysis, participants who were age 38 years or older at diagnosis had a higher rate of recurrence than younger participants (hazard ratio 2.85; 95% CI 1.10-7.38). This finding was the only significant association from the multivariate analysis and is illustrated using 2 Kaplan-Meier curves (Figure 2), showing that the five-year likelihood of recurrence is 31 percent for the older respondents and 15 percent for the young respondents.  

 

Peer Review Fig 2

 

Peer Review Table 3

Discussion

While many studies have looked at factors that influence meningioma recurrence, this was the first to systematically survey meningioma survivors, recruited through social media, about their experience. Typically, recurrence studies are based on a review of medical records; however, this study was conducted using an online survey of female survivors who belonged to a meningioma support group with the clear purpose of aiding other “patients like them.” Our results showed that older women had a higher risk of recurrence compared to younger women; race and ethnicity, meningioma grade, type of treatment and pregnancy history were not associated with an increased risk. Although the sample may not be generalizable widely, the findings reflect the experiences and burdens of the support group and have direct relevance for its members.

Although increasing age is a significant risk factor in the initial development of meningioma (12), its role in recurrence is less clear. Our study showed that the rate of recurrence for women age 38 years and older was significantly higher than that for women 37 years and younger. Some studies have reported a higher recurrence rate among the “younger” versus “older” patients in their sample; however, these samples typically included both males and females who represented a much older age range (28,42). In our study, the age span at diagnosis was 34-48 years and the majority of these women (86%) had not gone through menopause. It is possible that recurrence is higher in women in the latter years of childbearing age and shortly after menopause, as compared to women whose age falls on the younger (e.g., 20s-30s) or older (e.g., > 60) ends of the spectrum.

Tumor grade and form(s) of treatment were not shown to be significantly correlated with meningioma recurrence; however, our results could be due to selection bias of a younger, and possibly healthier, female-only population. Additionally, approximately one quarter of the sample reported “Not sure, don’t know” with regard to grade of meningioma. A review of the literature showed that higher grade tumors (WHO grades I-III) have a greater risk of recurrence and those that are more aggressively removed (Simpson grades I-IV) have a lower risk of recurrence, (27-29,31,50,55,64) albeit not always significant. (50,59).

Recurrence rates for all WHO grades have varied greatly in the literature, in part due to inclusion criteria (i.e., surgical results characterized by the Simpson grading system or the addition of radiation therapy), sample size, length of follow-up and were often reported as estimations based on similar statistical analyses as those used in this study.

WHO grade I tumors exhibit the lowest rate of recurrence, with estimated rates ranging from three to 26 percent at five years, and 13 to 32 percent at 10 years (48,60). WHO grade II tumors have a much higher rate of recurrence. Studies of patients with WHO grade II tumors who have undergone GTR report recurrence rates of approximately 30 percent at both five and 10 years (27,48); however, studies that included patients with either GTR or STR have ranged from 17- to 68-percent recurrence at five years and 13 to 77 percent at 10 years (21,27,66). WHO grade III meningiomas have the highest rate of recurrence, ranging from 52 to 100 percent within a 10-year timeframe (21,51,66).

Medications prescribed for meningioma are typically only for use as adjuvant therapy (e.g., chemotherapy, hormone suppressants) or to suppress symptoms (e.g., steroids, anticonvulsants). The majority of respondents in our study did not report taking medication(s) at the time of diagnosis; of those who did, steroids were most commonly reported and were not shown to be associated with recurrence.

The Roles of Pregnancy and Parity
Our results showed that pregnancy at any time following the initial diagnosis did not increase the risk of recurrence; conversely, it showed a slight protective effect, but this trend was not significant. Our numbers were too small to make generalizations about the effect of pregnancy contributing to the subsequent risk of recurrence over a longer period of follow up.

Additionally, we are unaware of any systematic studies on the relative or absolute risk of recurrence in pregnant women previously diagnosed with a meningioma, despite the multitude of studies that have looked at the role of pregnancy and parity at initial diagnosis (4,34,39,68). In many of those studies, pregnancy was not found to be a risk factor for meningioma (10,34,44).

Despite a lack of evidence, pregnancy and parity are often considered risk factors for meningioma. In a prior study, we found that women previously diagnosed with a meningioma often reported that “fear of recurrence” influenced their decisions on pregnancy (reference omitted for anonymity), suggesting that if the patients became pregnant as they desired, there would have been a significantly higher number of subsequent pregnancies. 

Limitations
This study has several limitations. First, the results were based on a small sample recruited from an online meningioma support group, and may not be representative of the experiences of all women who have been diagnosed with a meningioma, including those without Internet access. It is likely that those who have experienced a recurrence are more likely to join a meningioma support group than those who have not, resulting in an artificially higher rate of recurrence in this study as compared to some others. Second, approximately 96 percent of the respondents were non-Hispanic white women, and the results may not be generalizable to other racial/ethnic groups. Third, many respondents (29 out of 139) did not receive any surgical and radiation treatment, which led to their exclusion from the analysis.

Future research may examine whether this “watchful waiting” was due to inoperable location, patient preferences or lack of symptoms. Fourth, other factors, such as genetic predisposition, ionizing radiation and hormone replacement therapy, which have been shown to increase one’s risk of developing a meningioma, were not assessed due to survey length and measurement limitations. Fifth, the self-report survey did not include detailed questions on diagnosis (e.g., meningioma size, location and presenting symptoms) and treatment (e.g., Simpson grade), which may influence the risk of recurrence; hence, this report cannot be used to decide whether or not pregnancy would increase the chance of recurrence for a given patient. Additionally, roughly a quarter of the sample did not know their WHO tumor grade at diagnosis, which is one of the primary factors that determines recurrence.

Conclusions
This recurrence study was not meant to substitute in any way for the recommendations between a surgeon and his/her patient. For example, we cannot definitively comment on the role of subsequent pregnancy or parity on meningioma recurrence. Not all recurrences would be detected within the median follow-up (three years) reported in this study. However, this work may inspire future research that captures the outcomes of women of childbearing age diagnosed with meningioma. For example, using “patients like me” survey methods, an online risk calculator could be developed. Patients could input their information on their experiences and immediately benefit by conveniently and anonymously learning their risk(s) of meningioma recurrence. Simultaneously, their use of this calculator would further update and improve the calculator’s database to better inform future patients about their risks, enhancing precision medicine.

The findings of this patient-centered study are quite limited: among the female members of a meningioma support group, age at initial meningioma diagnosis influenced the risk of recurrence. Nevertheless, this study exemplifies patient-driven research that was conducted quickly, anonymously and affordably to address concerns important to a particular patient population.

Online social media provides a cost-effective medium to gather experiences from hard-to-reach patient groups to further clinical research, and can also be used to create novel tools (e.g., recurrence calculators) for the expedient delivery of information to members of support groups and future patients.


Benjamin M. Craig, PhD, of Moffitt Cancer Center in Tampa, Fla., and the department of economics at the University of South Florida; Michelle A. Owens, MA, of Health Outcomes and Behavior at the Moffitt Cancer Center; Damon R. Reed, MD, of the Sarcoma Program at the Moffitt Cancer Center; and Gerald F. Tuite, MD, FAANS, of the All Children’s Neuroscience Institute in St. Petersburg, Fla.

Disclosure: Funding support for this research was provided by an NCI R01 grant (omitted for anonymity) and the (omitted) Family Foundation. None of the authors have any conflict of interest that may affect the subject matter of this manuscript.

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