Neuropsychological functioning of children treated with intensive chemotherapy followed by myeloablative consolidation chemotherapy and autologous hematopoietic cell rescue for newly diagnosed CNS tumors: An analysis of the Head Start II survivors

Sands, Stephen A.; Oberg, Jennifer A.; Gardner, Sharon; Whiteley, Jennifer; Bender, Julia Glade; Finlay, Jonathan L.

doi:10.1002/pbc.22318

Cited by 48 publications

(58 citation statements)

References 45 publications

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“…Since the 'Head Start' trials began employing AuHCR with greater irradiation avoidance, we have documented improvements in quality of life by avoiding cranial irradiation, through prospectively conducted neuropsychological and quality of life follow-up studies. 23,24 To assess the side effects of AuHCR in the setting of the treatment of young children with newly-diagnosed malignant CNS tumors, we present the analysis of serious toxicities (grades III-V) in the first 100 days following transplant. Our data show a marked decrease in the rates of TRM, grade IV oropharyngeal mucositis and grade IV infection sequentially over the course of the 'Head Start' trials.…”

Section: Discussionmentioning

confidence: 99%

Decreased morbidity and mortality of autologous hematopoietic transplants for children with malignant central nervous system tumors: the ‘Head Start’ trials, 1991–2009

Altshuler

Haley

Dhall

et al. 2016

Bone Marrow Transplant

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Since 1991, three sequential prospective clinical trials have been conducted by the 'Head Start' (HS) Consortium in which young children with newly-diagnosed malignant central nervous system (CNS) tumors were treated with induction chemotherapy followed by single-cycle marrow-ablative chemotherapy and autologous hematopoietic rescue as a means of improving disease cure rate and quality of survival through avoidance (o 6 years old at diagnosis) or reduction (6-10 years old) of brain irradiation. Bone Marrow (HS I) or filgrastim-mobilized peripheral hematopoietic cells (HS II and III) were obtained following recovery from the first and/or second induction cycles. Radiotherapy was administered following all chemotherapy only for patients with residual tumor following completion of induction or with age greater than 6 years at diagnosis. Two hundred and twenty-six children were enrolled on three consecutive HS trials with primary malignant CNS tumors and underwent marrow-ablative chemotherapy. The 100-day treatment-related mortality (TRM) steadily declined as did grade IV transplant-related oropharyngeal mucositis. Factors most likely associated with the decrease in TRM and morbidity are increasing experience with the marrow-ablative chemotherapy regimen combined with improved leukapheresis and post-reinfusion supportive care techniques, contributing toward improved overall survival.Bone Marrow Transplantation (2016) 51, 945-948;

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Section: Discussionmentioning

confidence: 99%

Decreased morbidity and mortality of autologous hematopoietic transplants for children with malignant central nervous system tumors: the ‘Head Start’ trials, 1991–2009

Altshuler

Haley

Dhall

et al. 2016

Bone Marrow Transplant

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“…Less is known about the neurocognitive effects of systemic chemotherapy in the very young, which may be less toxic than irradiation [37], but still a contributing factor to deficits in executive functioning [38]. One study of outcome of children with brain tumors treated with high-dose chemotherapy found no significant association with age at diagnosis and neuropsychological outcome; however, there was a significant inverse relationship between time since diagnosis and full-scale IQ [39]. There is not enough evidence at this point to determine whether neurocognitive decline may continue in the years after chemotherapy in young children.…”

Section: Discussionmentioning

confidence: 99%

“…High-dose, marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) is a frontline treatment for brain tumors in very young children and believed to be less damaging than radiation therapy [6, 8]. There is evidence that chemotherapy leads to long-term brain tissue damage, including white [9] and gray matter loss [10], and neurocognitive deficits in children with acute lymphoblastic leukemia (ALL) [9, 11, 12]; however, in addition to systemic chemotherapy, these children received intrathecal chemotherapy with methotrexate (MTX) and/or cytosine arabinoside, drugs known to be neurotoxic, especially via instillation into cerebrospinal fluid (CSF).…”

Section: Introductionmentioning

confidence: 99%

Structural brain alterations in children an average of 5 years after surgery and chemotherapy for brain tumors

Nelson

Macey²,

Harper

et al. 2014

J Neurooncol

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Background Young children with brain tumors are often treated with high-dose chemotherapy after surgery to avoid brain tissue injury associated with irradiation. The effects of systemic chemotherapy on healthy brain tissue in this population, however, are unclear. Our objective was to compare gray and white matter integrity using MRI procedures in children with brain tumors (n=7, mean age 8.3 years), treated with surgery and high-dose chemotherapy followed by autologous hematopoietic cell rescue (AuHCR) an average of 5.4 years earlier, to age- and gender-matched healthy controls (n=9, mean age 9.3 years). Methods Diffusion tensor imaging data were collected to evaluate tissue integrity throughout the brain, as measured by mean diffusivity (MD), a marker of glial, neuronal, and axonal status, and fractional anisotropy (FA), an index of axonal health. Individual MD and FA maps were calculated, normalized, smoothed, and compared between groups using analysis of covariance, with age and sex as covariates. Results Higher mean diffusivity values, indicative of injury, emerged in patients compared with controls (p<0.05, corrected for multiple comparisons), and were especially apparent in the central thalamus, external capsule, putamen, globus pallidus and pons. Reduced FA values in some regions did not reach significance after correction for multiple comparisons. Conclusions Children treated with surgery and high-dose chemotherapy with AuHCR for brain tumors an average of 5.4 years earlier show alterations in white and gray matter in multiple brain areas distant from the tumor site, raising the possibility for long-term consequences of the tumor or treatment.

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“…Consequently, high-dose intravenous methotrexate (HD-MTX)–based chemotherapy regimens have been used as an alternative to CSI [6–8]. Young children with medulloblastoma treated on MTX-based regimens have shown improvement in progression free and overall survival [6–7, 9].…”

Section: Introductionmentioning

confidence: 99%

Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections

Wright

Panetta

Onar‐Thomas

et al. 2014

Cancer Chemother Pharmacol

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Purpose High-dose methotrexate (HD-MTX) has been used to treat children with central nervous system tumors. Accumulation of MTX within pleural, peritoneal, or cardiac effusions has led to delayed excretion and increased risk of systemic toxicity. This retrospective study analyzed the association of intracranial post-resection fluid collections with MTX plasma disposition in infants and young children with brain tumors. Methods Brain MRI findings were analyzed for postoperative intracranial fluid collections in 75 pediatric patients treated with HD-MTX and for whom serial MTX plasma concentrations ([MTX]) were collected. Delayed plasma excretion was defined as [MTX] ≥1μM at 42 hours (h). Leucovorin was administered at 42 h and then every 6 h until [MTX] <0.1μM. Population and individual MTX pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. Results Fifty-eight patients had intracranial fluid collections present. Population average (inter-individual variation) MTX clearance was 96.0 ml/min/m2 (41.1 CV%) and increased with age. Of the patients with intracranial fluid collections, 24 had delayed excretion; only 2 of the 17 without fluid collections (p<0.04) had delayed excretion. Eleven patients had grade 3 or 4 toxicities attributed to HD-MTX. No significant difference was observed in intracranial fluid collection, total leucovorin dosing, or hydration fluids between those with and without toxicity. Conclusions Although an intracranial fluid collection is associated with delayed MTX excretion, HD-MTX can be safely administered with monitoring of infants and young children with intracranial fluid collections. Infants younger than one year may need additional monitoring to avoid toxicity.

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Neuropsychological functioning of children treated with intensive chemotherapy followed by myeloablative consolidation chemotherapy and autologous hematopoietic cell rescue for newly diagnosed CNS tumors: An analysis of the Head Start II survivors

Cited by 48 publications

References 45 publications

Decreased morbidity and mortality of autologous hematopoietic transplants for children with malignant central nervous system tumors: the ‘Head Start’ trials, 1991–2009

Decreased morbidity and mortality of autologous hematopoietic transplants for children with malignant central nervous system tumors: the ‘Head Start’ trials, 1991–2009

Structural brain alterations in children an average of 5 years after surgery and chemotherapy for brain tumors

Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections

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