SEX AS PROGNOSTIC FACTOR IN PEDIATRIC GLIOMAS

Children undergoing surgery for high-grade glioma (HGG) have an increased chance of survival when tumors are fully removed, a new study confirms.

In addition, female patients survived almost 6 years longer than male patients who underwent the same procedure, suggesting sex-specific differences in the development of these tumors.

"These patients' tumors presented identically and were treated identically, but the children had very different outcomes," said Jeffrey P. Greenfield, MD, PhD, associate professor of neurological surgery at Weill Cornell Medical College in New York, New York, and lead author of the study. "It's early, but I think this opens up really exciting possibilities for exploring the differences in gene expression between boys and girls with brain tumors."

The paper, published online August 18 and appears in the September issue of Neurosurgery, affirms gross total resection (GTR) or the surgical removal of all visible cancer, as the standard of care in HGG.

However, the unexpected difference in overall survival (OS) between the sexes provides "compelling evidence that GTR is even more critical in female patients," Dr Greenfield noted.

Complete Resection Yields Better Overall Survival

Patients diagnosed with HGG, a particularly aggressive type of brain tumor, have a historically poor prognosis, with a 2-year survival rate of only 45%. Although deadly, however, the incidence of HGG is less than 1 in 100,000 children (ages 0 to 19 years) and is nearly equally divided between males and females.

In the retrospective study, believed to be the largest of its kind, Dr Greenfield and colleagues identified 97 patients at Weill Cornell and Memorial Sloan-Kettering treated for HGG between 1988 and 2010. The patients, who were aged 21 years or younger at the time of diagnosis, included 43 females and 54 males and had a median age of 11 years.

Investigators gathered information, including age at diagnosis, sex, histologic tumor type, tumor location, extent of initial resection, date of recurrence/ progression, date of death or last follow-up, and adjuvant treatment with radiation or chemotherapy.

Thirty-two patients (33%) underwent GTR, determined from the postoperative imaging report or from the clinical record.

Although the median OS was only 1.6 years (95% confidence interval [CI], 1.1 - 2.3 years) for patients receiving subtotal resection (STR), for children in whom GTR was achieved, median OS improved to 3.4 years.

However, improvement in survival with complete resection differed dramatically by sex.

While both males and females showed a benefit from more aggressive surgery, the benefit of GTR for female patients appeared to be much greater than that for male patients, researchers reported.

Females undergoing GTR had an OS of 8.1 years (95% CI, 2.9 - no upper limit) compared with 1.4 years for all other females (95% CI, 1.1 - 2.6), while males with GTR had an OS of 2.4 years (95% CI, 1.0 - 4.0) vs 1.4 years for other males (95% CI, 0.9 - 1.9) (P = .001).

As Dr Greenfield explained, OS significantly correlated with the location of the tumor as well. Researchers also noted a trend toward longer OS in children younger than 3 years and those older than 13 years, but this did not achieve statistical significance (P = .16).

"Our study provides strong evidence in support of an attempt at GTR over STR or biopsy, and demonstrates that age, tumor location, and sex are important prognostic factors in pediatric HGG," Dr Greenfield and colleagues write. "Additionally, our article…raises several intriguing questions as to the potential genetic and epigenetic heterogeneity of these tumors, not only between adults and children, but also between sexes."

With future studies, investigators hope to resolve the questions surrounding the varying mechanisms of response to treatment and emphasized that analysis of genetic subtypes and molecular markers will play a critical role in their research.

"This is one example of an accidental discovery that's raised some interesting questions and challenged accepted dogma that we're now exploring," Dr Greenfield concluded. "Hopefully, preliminary data will be available soon that will shed light on this fascinating gender difference."

One author was supported by the St. Baldrick's Foundation Summer Fellowship, Childhood Brain Tumor Foundation, and Musella Foundation for Brain tumor Research. Dr Greenfield has disclosed no relevant financial relationships.

Neurosurgery. 2015;77:443-453. Abstract