Comparison of Physiologic Growth Hormone Replacement Therapy to No Replacement on Craniopharyngioma Recurrence in Pediatric Patients

Background: Transsphenoidal resection of craniopharyngiomas can result in deficiency of a multitude of pituitary axes. In the pediatric population, Growth Hormone deficiency can result in impaired organ maturation. Significant controversy exists on whether Growth Hormone Replacement Therapy (GHRT) contributes to the recurrence of craniopharyngiomas in the pediatric population, and may place patients at a higher risk of tumor growth. We set out to determine the cumulative experience available in the literature regarding the perioperative management of this disease process.

Objective: A systematic review and meta-analysis were conducted to examine the effect of GHRT on the recurrence of craniopharyngiomas.

Methods: PubMed, EMBASE, and Cochrane databases were searched through October 2015 for studies that evaluated the effect of GHRT on the recurrence of pediatric craniopharyngiomas. Pooled effect estimates were calculated using fixed- and random-effects models.

Results: After excluding 303 duplicate studies, 797 articles were identified for screening titles and abstracts; of these, 78 studies were selected for full text review. Eight studies (n = 2,160 patients) met all inclusion criteria, including one retrospective cohort and seven case series. Two studies included two groups of pediatric patients, those with or without GHRT. Overall, 2,155 pediatric patients were treated with GHRT after surgery and 12 were not (age 1.3–17.8 years; 57–84% male). Surgical approach was either subfrontal alone (5 patients) or transnasal-transsphenoidal (13 patients). The frequency of GH replacement therapy was either daily (29 patients), 3 times/week (23 patients), or 6 times/week (488 patients). GHRT duration ranged between 1.9 and 5 years and the average post-diagnosis administration was 2.4 years. The overall craniopharyngioma recurrence rate was lower among children who were treated by GHRT (11.7%; 95% CI: 10.4%; 13.2%; fixed-effects model; I2 = 88.6%; P-for heterogeneity <0.01; n = 8 groups) compared with those who were not (43.1%; 95% CI: 16.7%; 74.1%; I2 =61.7%; P-for heterogeneity = 0.11; n = 2), although the p-value comparing the two groups was non-significant (p = 0.23). Among patients who were treated by GHRT, subgroup analysis based on multiple centers showed a statistically significant lower tumor recurrence rate (10.4%; 95% CI: 9.10%; 11.8%; I2 = 82.0%; P-for heterogeneity <0.01; n = 3) than single-center studies (37.9%; 95% CI: 27.3%; 49.7%; I2 = 54.4%; P-for heterogeneity =0.07; n = 5) (P-interaction <0.01). Further stratification by study quality and journal impact factor did not demonstrate a statistically significant difference among these groups (p > 0.05 for both). Results from the random-effects model were not materially different from the fixed-effects model. Both Begg’s rank correlation test (p = 1.00) and Egger’s linear regression test (p = 0.24) indicated no publication bias.

Conclusion: GHRT in the setting of pre-existing intracranial tumors remains a topic of controversy in the pediatric literature. Our current meta-analysis demonstrates that pediatric patients treated with GHRT after surgical resection of craniopharyngioma have a lower incidence of tumor recurrence.

Running Head: Effect of growth hormone replacement therapy on the recurrence of pediatric craniopharyngioma after brain tumor surgery: a meta-analysis.

Keywords: growth hormone, somatotrophic hormone, hormone replacement therapy, pediatric craniopharyngioma, craniopharyngioma recurrence