Lifestyle and subsequent meningioma in childhood cancer survivors: A report from the St. Jude Lifetime Cohort study

Abstract Background Lifestyle is associated with meningioma risk in the general population. Aims We assessed longitudinal associations between lifestyle‐associated factors and subsequent meningiomas in childhood cancer survivors. Methods and results Childhood cancer survivors age ≥18 years in the St. Jude Lifetime Cohort Study were evaluated for body composition, self‐reported physical activity, cardiopulmonary fitness, muscle strength, smoking, and alcohol consumption at baseline. Time to first meningioma analyses were performed, adjusted for sex, age at diagnosis and baseline assessment, treatment decade, and childhood cancer treatment exposures. The study included 4,072 survivors (47% female; [mean (SD)] 9 (6) years at diagnosis; 30 (8.5) years at the start of follow‐up, with 7.0 (3.3) years of follow‐up). 30% of the participants were survivors of acute lymphoblastic leukemia and 29% of the participants had received cranial radiation. During follow‐up, 90 participants developed ≥1 meningioma, of whom 73% were survivors of acute lymphoblastic leukemia, with cranial radiation being the strongest risk factor (relative risk [RR] 29.7, 95% confidence interval [CI] 10.6‐83.2). Muscle strength assessed by knee extension was associated with a lower risk of developing a meningioma in the adjusted analyses (RR 0.5, 95% CI 0.2‐1.0, p = 0.04 for quartiles 3‐4 vs. 1). No other lifestyle‐associated variable was associated with subsequent meningioma. Conclusion Independent of cranial radiation, muscle strength was associated with a lower risk of developing a subsequent meningioma in childhood cancer survivors.


| Physical activity
Physical activity was self-reported as moderate-to-vigorous physical activity minutes per day, which was then converted into metabolic equivalent task (MET) hours per week and categorized into 0-3, 3-6, and ≥6 METh/week.0-3 MET hours per week was used as reference.

| Smoking
Self-reported smoking, categorized as never, previous, or current smoking.Current smoking was used as reference in the analyses.

| Alcohol consumption
Risky drinking was defined as >3 drinks per day or >7 per week for women, >4 per day or >14 per week for men.Risky drinking was used as reference in the analyses.

| Outcome
Time to first meningioma during survivorship in adult age was the outcome, including both benign and malignant meningiomas.Only meningiomas occurring after the baseline assessment were included.All SJLIFE participants have ascertained follow-up of subsequent malignancies through medical record abstraction and yearly follow-up with the St Jude Cancer Registry. 11There is no routine CNS-imaging included in the research evaluations in SJLIFE.Hence, all meningiomas were diagnosed from clinically motivated follow-up.Meningioma diagnoses were ascertained from histopathological diagnosis where available and otherwise from imaging.

| Treatment exposures
Medical record abstraction for eligible SJLIFE participants includes abstraction of all chemotherapy received, including cumulative doses. 11In this study, we included dichotomized treatment exposures (yes/no) to anthracyclines, alkylating agents, epipodophyllotoxins, platinum, and brain radiation.

| Statistical methods
Piecewise exponential models estimated risk for meningioma as relative risk (RR) with 95% confidence interval (CI) adjusted for sex, age T A B L E 1 Demographic, lifestyle, diagnosis, and treatment variables according to body composition.

| Univariate analyses
In the univariate analyses, self-reported physical activity was not associated with the subsequent risk of developing meningioma (RR 0.

| Multivariable models
As expected, cranial radiation exposure was the strongest risk factor for developing meningiomas in this childhood cancer survivor population (RR 29.7, 95% CI 10.6-83.2).In our multivariable models including treatment variables, knee extension strength was the only lifestyle variable associated with the risk of developing a subsequent meningioma (RR 0.5, 95% CI 0.2-1.0 for quartiles 3-4 vs. 1, Table 2).None of

| DISCUSSION
In this observational study of 4072 childhood cancer survivors, we report a protective association between knee extension strength and the risk of developing meningioma, independent of cranial radiation therapy.Previous studies have reported increased risk of meningioma with increasing body fat and physical inactivity in the general population. 1,2r study could not confirm associations between self-reported physical activity or BMI and meningioma.There are several possible explanations for this difference.Childhood cancer survivors are at increased risk of sarcopenic obesity and BMI is a poor measure for identifying obesity in childhood cancer survivors, compared to DEXA. 12 This might reflect the difference in RR between BMI-and DEXA-assessed obesity, albeit none of them were significant after adjustment for treatment exposures and other potential confounders.Self-reported physical activity measures have relatively low sensitivity in the general population. 13Objectively assessed cardiorespiratory and muscular fitness are more sensitive measures and are improved mainly by exercise training and less by low-intensity PA, 14 and have been reported to be stronger predictors of other health outcomes, such as all-cause mortality. 14A recently published study showed associations between cardiorespiratory fitness and site-specific cancers across several organ systems but did not look at meningiomas specifically. 15In our univariate analyses, both favorable body composition and all measures of cardiorespiratory and musculoskeletal fitness were associated with decreased risk of developing meningioma.Our multivariable analyses could only confirm associations for knee extension strength.This might be explained by residual confounding from cranial radiation treatment but may also reflect true associations between, for example, exercise and meningiomas.This should be further assessed in studies from other cohorts and in future studies with longer follow-up.Since T A B L E 2 Hazard rate ratios for associations between lifestyle-associated variables and meningioma.cranial radiation increases the risk of both meningioma and obesity, it can be hard to discriminate possible direct effects of obesity on meningioma.It is also possible that some of the results, for example, for DEXA-assessed body composition suffered from low statistical power.Most survivors who developed a meningioma did not undergo DEXA scans and a longer follow-up might result in significant associations.The fact that all associations for body composition and fitness were in the expected direction, albeit not significant, could imply that a longer follow-up with more meningiomas during follow-up would yield further significant associations.There is a long-time latency between childhood cancer treatment and meningioma onset.Our population was followed from a mean of 22-28 years after diagnosis, corresponding to the peak in meningioma incidence in other studies. 4is study was performed within Stephanie B. Dixon: Conceptualization (supporting); investigation (equal); methodology (supporting); writingreview and editing (equal).Matthew D. Wogksch: Investigation (supporting); methodology (supporting); writingreview and editing (supporting).Matthew J. Ehrhardt: Conceptualization (supporting); investigation (supporting); methodology (supporting); writingreview and editing (supporting).Gregory T. Armstrong: Conceptualization (supporting); investigation (supporting); methodology (supporting); project administration (equal); resources (equal); writingreview and editing (supporting).Melissa M. Hudson: Conceptualization (supporting); funding acquisition (equal); investigation (supporting); methodology (supporting); resources (supporting); writingreview and editing (supporting).Kirsten K. Ness: Conceptualization (equal); funding acquisition (equal); investigation (equal); methodology (equal); project administration (equal); resources (equal); supervision (lead); writingreview and editing (equal).