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Survival Differences Between Males and Females Diagnosed With Childhood Cancer

Abstract Background Males have worse survival for childhood cancer, but whether this disparity exists among all childhood cancer types is undescribed. Methods We estimated sex differences in survival for 18 cancers among children (0–19 years) in Surveillance, Epidemiology, and End Results 18 (2000–2014). We used Kaplan-Meier survival curves (log-rank P values) to characterize sex differences in survival and Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between sex and death for each cancer type. We used an inverse odds weighting method to determine whether the association between sex and death was mediated by stage of disease for solid tumors. Results Males had worse overall survival and a higher risk of death for acute lymphoblastic leukemia (HR = 1.24, 95% CI = 1.12 to 1.37), ependymoma (HR = 1.36, 95% CI = 1.05 to 1.77), neuroblastoma (HR = 1.28, 95% CI = 1.09 to 1.51), osteosarcoma (HR = 1.29, 95% CI = 1.08 to 1.53), thyroid carcinoma (HR = 3.25, 95% CI = 1.45 to 7.33), and malignant melanoma (HR = 1.97, 95% CI = 1.33 to 2.92) (all log-rank P values < .02). The association between sex and death was mediated by stage of disease for neuroblastoma (indirect HR = 1.12, 95% CI = 1.05 to 1.19), thyroid carcinoma (indirect HR = 1.24, 95% CI = 1.03 to 1.48), and malignant melanoma (indirect HR = 1.28, 95% CI = 1.10 to 1.49). For these six tumors, if male survival had been as good as female survival, 21% of male deaths and 13% of total deaths after these cancer diagnoses could have been avoided. Conclusions Consideration of molecular tumor and clinical data may help identify mechanisms underlying the male excess in death after childhood cancer for the aforementioned cancers.

Cancer continues to be a leading cause of death among children and adolescents, particularly those aged 5-14 years (1). Survival differences between childhood cancer types are welldocumented with central nervous system and bone tumors resulting in lower survival and acute lymphoblastic leukemia (ALL) and lymphomas having higher survival rates (2)(3)(4). In epidemiologic survival analyses, males and females are traditionally grouped together to estimate survival percentages, and sex-adjusted hazard ratios (HRs) for the risk of death from childhood cancer are often presented. However, even though males have worse survival than females for childhood cancer overall, there is little information on sex differences in survival by cancer type, making it unclear whether the sex variation observed for childhood cancer survival overall extends to individual childhood tumor types (2,5,6).
The identification of sex differences in survival after a childhood cancer diagnosis may be helpful in uncovering biological mechanisms responsible for the increased risk of death among males. These findings may also help guide future research to identify treatments that may have greater benefit in male or female children as done among adults, where sex differences in tumor genomics were used to identify clinically actionable therapies with potential sex-specific benefits (7). The survival differences between sexes are likely to be multifactorial depending on features such as sex differences in diagnosis delay (8), pharmacogenetics (9)(10)(11)(12), and/or cancer biology. To identify cancer types with sex differences in survival and to determine whether these differences depend on stage of disease, we used the Surveillance, Epidemiology, and End Results (SEER) Program 18 registries (2000Program 18 registries ( -2014 to conduct a survival analysis for 18 childhood cancers (13). We characterized sex differences in overall survival and estimated the risk of death for males relative to females for each cancer. We then conducted a mediation analysis for the association between sex and death, treating stage of disease as a mediator.

Study Population
Cancer cases (n ¼ 57 004) aged 0-19 years were identified using the SEER Program 18 registries. Cases included in SEER 18 (14) (2000-2014) arise from Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, Utah, Los Angeles, San Jose-Monterey, rural Georgia, the Alaska Native Tumor Registry, greater California, greater Georgia, Kentucky, Louisiana, and New Jersey. To be included in this analysis, individuals must have had a microscopically confirmed first primary tumor classified as one of the main International Classification of Childhood Cancer [3rd edition (13)] types that had at least 500 cases (n ¼ 45 229) available for analysis. Additional tumor types excluded were germ cell tumors, because these arise from different cell types in males and females and survival differences have been characterized elsewhere (15), and tumors with "other" classifications (Supplementary Table 1, available online). Of the cases identified in SEER for this analysis, 47 were missing survival time and were not included in the survival analyses.

Cancer Type
The International Classification of Childhood Cancer categories included in the current analysis were I Leukemias (Ia Acute lymphoid leukemia, Ib Acute myeloid leukemia), II Lymphomas (IIa Hodgkin lymphoma, IIb Non-Hodgkin lymphoma, IIc Burkitt lymphoma), III

Variables of Interest
From SEER we obtained age at diagnosis (<1, 1-4, 5-9, 10-14, 15-19 years), year of diagnosis (2000-2004, 2005-2009, 2010-2014), race or ethnicity (non-Hispanic, white, black, Asian or Pacific Islander, Hispanic), tumor size (<2 cm, 2 to <5 cm, !5 cm; not available for I Leukemias or II Lymphomas), stage of disease (local, regional, distant; not available for I Leukemias), metastases (yes or no; not available for I Leukemias or II Lymphomas), months of survival (defined in SEER using the date of diagnosis to the date of death from any cause or last contact by the study end date of December 31, 2014), and vital status.

Statistical Analysis
Five-year survival percentages stratified by sex for each cancer type were estimated. Kaplan-Meier survival curves and log-rank P values to identify statistically significant sex differences in overall survival were generated. We used Cox proportional hazards models to estimate hazard ratios and the corresponding 95% confidence intervals (CIs) for the association between male sex, relative to female sex, and death for each cancer. There was no violation of the proportional hazards assumption when considering an interaction term between sex and time in the models. Age-stratified analyses for the association between sex and death were carried out using age at diagnosis categories: 0-4, 4-9, 10-14, and 15-19 years. A P value was calculated for each cancer through use of an age-sex interaction term in each model.
For solid cancers with a statistically significant sex difference in survival, we conducted a mediation analysis to determine if the association between sex and the risk of death after a cancer diagnosis was mediated by stage of disease using an inverse odds weighting method (16)(17)(18)(19). Briefly, the inverse odds weighting Cox proportional hazards model allows for estimation of the association between sex and death, independent of stage of disease. The weight for sex was estimated from a logistic regression model for stage of disease in association with sex where the reference category, female, was assigned the weight of 1. Males were assigned a value of the inverse odds of the aforementioned logistic models conducted separately for each cancer. The indirect effect of sex on death operating through stage of disease was calculated by subtracting the direct effect beta from the total effect beta (b indirect ¼ b total À b direct ). For the total, direct, and indirect effects, the resulting hazard ratios were estimated, and bootstrapped standard errors (1000 replications) were used to estimate the 95% confidence intervals. A statistically significant indirect effect was interpreted as evidence of mediation by stage of disease for the association between sex and death.

Results
The distribution of age, race, tumor size, stage of diseases, metastases at diagnosis, vital status, and year of diagnosis by sex for each cancer is in Table 1. Males comprised 53% of the study sample (results not shown). Tumors with a female predominance included nephroblastoma (48% male, 52% female), thyroid carcinoma (19% male, 81% female), and malignant melanoma (43% male, 57% female). The race or ethnicity distribution of cases was similar between sexes for each cancer. Among children with solid cancers and tumor size available, there were few sex differences except Ewing sarcoma, where males more frequently had tumors larger than 5 cm (79% male, 70% female) and PNETs where males less frequently had tumors larger than 5 cm (48% male, 57% female). For stage of disease, differences in the distribution by sex emerged among some cancers. Males were more frequently diagnosed with distant stage of disease for Hodgkin lymphoma (40% male, 33% female), neuroblastoma (56% male, 49% female), and osteosarcoma (24% male, 20% female). Conversely, males were less frequently   diagnosed with local disease for thyroid carcinoma (45% male, 51% female) and malignant melanoma (78% male, 83% female).
The hazard ratios and 95% confidence intervals for male sex, relative to female sex, and the risk of death were elevated for ALL (HR ¼ 1.24, 95% CI ¼ 1. 12    were generally consistent in direction and magnitude of association in models adjusted for age at diagnosis, race or ethnicity, year of diagnosis, and stage of disease, where applicable. Because age at diagnosis may modify the association between sex and death for some childhood cancers, we conducted age-stratified analyses. There was heterogeneity in the association between sex and death by age at diagnosis for some cancers (Table 3). Elevated hazard ratios that excluded the null were observed for males aged 0-4 years for ependymoma (HR ¼ 1.44, 95% CI ¼ 1.02 to 2.02) and neuroblastoma (HR ¼ 1.25, 95% CI ¼ 1.03 to 1.50). Among children aged 5-9 years at diagnosis, there was an elevated risk of death among males for ALL (HR ¼ 1.28, 95% CI ¼ 1.01 to 1.62). In adolescents aged 10-14 years at diagnosis, male sex was associated with an increased risk of death for neuroblastoma (HR ¼ 2.39, 95% CI ¼ 1.18 to 4.81). For teens aged 15-19 years, male sex was associated with an increased risk of death for Ewing sarcoma (HR ¼ 1.53, 95% CI ¼ 1.05 to 2.21), thyroid carcinoma (HR ¼ 5.03, 95% CI ¼ 1.89 to 13.40), and malignant melanoma (HR ¼ 2.72, 95% CI ¼ 1.67 to 4.43). Estimates were similar in magnitude and direction when all models were adjusted for race and year at diagnosis (results not shown).
As stage of disease lies on the temporal path between sex and death following a childhood cancer diagnosis, we conducted a mediation analysis treating stage of disease as a mediator for ependymoma, neuroblastoma, osteosarcoma, thyroid Table 3. Hazard ratios and 95% confidence intervals for the association between male sex and the risk of death by cancer type stratified by age at diagnosis category, Surveillance, Epidemiology, and End Results 18 (2000Results 18 ( -2014 Age at diagnosis category  carcinoma, and malignant melanoma (Table 4), which comprised the solid tumors that displayed statistically significant total associations between sex and death. In the first-leg analyses (Supplementary Table 4, available online), male sex was strongly associated with distant stage of disease for neuroblastoma, osteosarcoma, and malignant melanoma. The mediation results (

Discussion
We observed sex differences in survival for a number of pediatric malignancies using the SEER 18 registries. Males had worse overall survival than females, as others have observed (2,5,6). We and others have reported worse survival and an increased risk of death for males diagnosed with ALL (21-23), ependymoma, neuroblastoma, osteosarcoma (24), thyroid carcinoma (25), and malignant melanoma (26,27). We note that the thyroid carcinoma results arise from a very small number of events (n ¼ 25); thus, these results should be interpreted with caution. We observed slight variation in the association between sex and death by age at diagnosis for ALL, ependymoma, neuroblastoma, osteosarcoma, thyroid carcinoma, and malignant melanoma. Importantly, we estimated that one in five male deaths after a diagnosis with ALL, ependymoma, neuroblastoma, osteosarcoma, thyroid carcinoma, or malignant melanoma could have been avoided if males experienced survival as good as females in this population during the study period.
For neuroblastoma, thyroid carcinoma, and malignant melanoma, we found evidence of mediation by stage of disease for the association between sex and death. Notably, 44%, 18%, and 37% of the observed sex differences in the risk of death for neuroblastoma, thyroid carcinoma, and malignant melanoma, respectively, operated through stage of disease in our study. Our findings suggest that factors other than stage of disease at diagnosis may also contribute to the sex differences in survival and risk of death after a childhood cancer diagnosis.
Although the purpose of this study was to identify survival differences between males and females diagnosed with childhood cancer when considering individual tumor types, there are a number of possible mechanisms underlying the male excess in death that may be relevant across cancer types and warrant further study in more appropriate datasets. The identification of sex differences in diagnosis delay, treatment response, tumor biology, or even treatment received may provide insight into the biological and/or social mechanisms underlying the observed male excess in death. In a review article characterizing diagnosis delay for childhood cancer, there was some evidence of a delay in diagnosis for males compared with females, particularly for Ewing sarcoma (28), which we found to differ by sex in tumor size, 5-year survival, and the risk of death among older children (8). However, the scarcity of literature examining the delay in diagnosis for all cancer types using modern cancer classifications and adequate sample sizes highlights the necessity for further investigation into this factor as a potential mechanism for the male excess in death following childhood cancer.
Sex differences in pharmacogenetics may also affect the pharmacokinetics of therapies in male and female children as observed in adults where pharmacokinetic sex differences of up to 40% have been reported (9)(10)(11). Although drug development generally focuses on overall therapeutic efficacy, it may be beneficial to also consider sex differences in the response to current and new therapies. In past, present, and future clinical trials, this could be done by comparing and contrasting the therapeutic responses between boys and girls through sex-stratified analyses.
Sex differences in tumor biology may be an important factor in the observed sex differences in survival after a childhood cancer diagnosis. Concerning ALL, where we observed the strongest increased risk of death among males for children aged 5-9 years at diagnosis, there are known differences the distribution of cytogenomic subtypes by age at diagnosis (29), which also have differing prognoses (30,31). However, there is little information available on sex differences in ALL subtypes, particularly the cytogenomic subtypes. With regard to ALL immunophenotype, Tcell ALL, diagnosed in up to 15% of ALL cases, is twice as common among males and is associated with worse outcomes than B-cell ALL (31)(32)(33). This sex difference may contribute to the observed increased risk of death among males.
Although ALL has the most well-characterized subtypes of the pediatric tumors with an increased risk of death in males, molecular subtypes with prognostic differences have been identified in neuroblastoma (34), namely, ploidy and MYCN status, and ependymoma, which displays sex differences in subtype (3,35); however, subtypes for osteosarcoma have failed to replicate across studies (36). Molecular subtypes for thyroid carcinoma and malignant melanoma are less often characterized. As such, research on sex differences in childhood cancer subtypes may shed light on the contribution of sex differences in tumor biology to the observed survival differences between males and females.
Even though our findings for the association between sex and the risk of death after cancer diagnosis arise from a large, population-based dataset for the main childhood cancers using modern definitions, our study should be interpreted with the following limitations in mind. SEER does not have complete or detailed treatment data (37) for cases; therefore, we considered stage of disease to be a potential mediator of the association between sex and the risk of death. Because stage is routinely collected by cancer registries contributing to SEER (38), we hypothesized that stage of disease may serve as a surrogate for treatment received. Treatment received is usually determined by risk stratification for pediatric cancers, which generally depends on age, tumor characteristics (ie, size or molecular subtype), and stage of disease but not sex (3,4,34,36). Clinical studies with detailed treatment and stage data are well-suited to study sex differences in treatment received and should consider treatment as a mediator between sex and death in the future. Characterizing sex differences in survival by tumor subtypes or risk groups is beyond the scope of this analysis, but studies with detailed subtype data, such as the MLL-rearranged or ETV6-RUNX1 subtypes of ALL or the MYCN status and risk group information for neuroblastoma, would be well-suited to examine these associations (30,39). Finally, consideration of insurance status, which may affect access to care and care utilization, should be evaluated in studies with adequate insurance information to determine the role of insurance status in the observed sex differences in pediatric cancer survival. Because this information is not available in SEER for cases diagnosed before 2007, this was not considered in our analyses.
In conclusion, we observed sex differences in survival for ALL, neuroblastoma, ependymoma, osteosarcoma, thyroid carcinoma, and malignant melanoma using the SEER 18 registries. These six tumor types combined account for approximately one-third of cancer diagnoses among children and adolescents (5) and almost 40% of deaths in SEER data. Approximately 21% of male deaths and 13% of total deaths due to ALL, neuroblastoma, ependymoma, osteosarcoma, thyroid carcinoma, and malignant melanoma could have been avoided if males experienced survival rates equal to those observed among females during the study period. The observed sex differences in survival may depend to some degree on stage of disease but may also depend on factors such as sex differences in diagnosis delay, tumor biology, and receipt and response to treatment, which should be investigated in epidemiologic or clinical studies with detailed molecular tumor and clinical data.