Late effects in children treated with intensive multimodal therapy for high-risk neuroblastoma: High incidence of endocrine and growth problems

Abstract

Due to the poor prognosis of high-risk (HR) neuroblastoma (NBL), scant data exist on late effects after treatment. Recently, protocols utilizing intense multimodal treatment have resulted in improved long-term survival. The objective of this study was to determine the prevalence of late effects in survivors of HR NBL. A retrospective review of clinical data for serial patients completing treatment between September 1994 and October 2007 and surviving for at least 1 year was performed. Therapy included aggressive chemotherapy, surgery, radiation and single or tandem SCT. Oncology follow-up was standard; clinical criteria were utilized for referrals to endocrinology and other services. Fifty-one eligible patients were identified. Median follow-up was 6.1 years (range 1.0-15.2). Height was significantly impacted (DZ-score À 1.91 in those treated with TBI and À 0.77 in those without). Pre-diabetes or diabetes, hypothyroidism and ovarian insufficiency were observed in 50, 59 and 75% of at-risk survivors, respectively. Hearing loss and dental issues were common. Nine patients had relapse of NBL; seven died of progressive disease. As there is a high prevalence of late effects in long-term survivors of HR NBL, close monitoring and further studies after treatment are indicated, and in particular after more modern, non-TBI regimens.

Overview and recent advances in the treatment of neuroblastoma

“…Effects on the endocrine system also create growth hormone deficiency, hypothyroidism, insulin resistance, premature ovarian failure and delayed puberty [163]. Most of these endocrinopathies are seen in the high-risk neuroblastoma group and are increased with use of total body irradiation (TBI) [163,167].…”

“…Musculoskeletal changes as a result of therapy, primarily scoliosis and osteoporosis, can decrease linear growth [163,167]. Effects on the endocrine system also create growth hormone deficiency, hypothyroidism, insulin resistance, premature ovarian failure and delayed puberty [163].…”

“…High-frequency hearing loss may affect up to 73% of individuals treated [163]. A study of European survivors found that nearly half of patients developed hearing loss, and 9% had severe hearing loss (Brock grade 3 and 4), often requiring the use of hearing aids [164].…”

Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy with Microtubule Drugs

“…Children with relapsed/refractory neuroblastoma have a <10% chance of survival (1). In addition, an increasing number of neuroblastoma survivors develop multisystem deficiencies (2) and secondary malignancies (3) as a result of the toxic chemotherapy exposures. Thus, novel therapies are urgently needed for these children.…”

Childhood Cancer Treatments and Associated Endocrine Late Effects: A Concise Guide for the Pediatric Endocrinologist

“…Children treated with 13-cis-retinoic acid for neuroblastoma may have irreversible damage to their growth plates and are at risk of significantly impaired final adult height [59]. Hedgehog pathway inhibitors, used in clinical trials to treat a subset of patients with malignancies believed to be driven by the aberrant activation of this pathway, have recently been shown to also cause growth plate damage and premature epiphyseal fusions [60].…”