Osteonecrosis in Children After Therapy for Malignancy

Kaste, Sue C.; Karimova, Evguenia J.; Neel, Michael D.

doi:10.2214/ajr.10.6073

Cited by 44 publications

(46 citation statements)

References 75 publications

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“…4, 6, 9, 10 Our prospective findings in this trial demonstrate that the use of alternate-week rather than continuous dexamethasone during delayed intensification results in a two-fold reduction in the relative risk of symptomatic ON among rapid responder patients ≥10 years old, particularly those 16+ years old, and a four-fold reduction among those randomized to intensified therapy, even though those treated with alternate week dexamethasone received a higher total dexamethasone exposure (Figures 4A-4C). Additionally, osteonecrosis incidence was lower among slow responder patients ≥10 years old assigned to double delayed intensification with alternate-week dexamethasone on this study, as compared to a similar historical cohort treated on the prior CCG-1882 trial who received two delayed intensification phases with continuous dose dexamethasone (11·8% versus 23·2%).…”

Section: Discussionmentioning

confidence: 99%

Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial

Mattano

Devidas

Nachman

et al. 2012

The Lancet Oncology

151

171

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SUMMARY Background Acute lymphoblastic leukemia (ALL) is curable in over 80% of children and adolescents with high-risk features. However, current therapies are associated with symptomatic osteonecrosis that disproportionately affects adolescents, often requires surgery, and is one of the most common causes of short- and long-term morbidity. A strategy is needed to lessen this risk. Methods CCG-1961, a multi-cohort randomized cooperative group trial, evaluated components of therapeutic intensification in 2056 eligible, newly diagnosed high-risk patients (white blood cell count ≥50×109/L and/or age ≥10 years). To address osteonecrosis, a novel alternate-week dexamethasone schedule (10 mg/m2/day on days 0-6 and 14-20) was compared to standard continuous dexamethasone (10 mg/m2/day on days 0-20) in randomized regimens with either double or single delayed intensification phases, respectively. Randomization was done based on a randomization schedule generated using permuted blocks within strata. Patients were prospectively monitored clinically for osteonecrosis, with confirmatory imaging of suspected sites. Primary analyses were performed on an intent-to-treat basis and focused on the estimation and comparison of cumulative incidence rates of osteonecrosis both overall and in patient subgroups (age, gender, marrow early response status); final results are herein reported. This study is registered with ClinicalTrials.gov, number NCT00002812. Findings Symptomatic osteonecrosis was diagnosed in 143 patients at 377 confirmed skeletal sites, resulting in 139 surgeries. The overall cumulative incidence of osteonecrosis was 7·7% (N=2056) at 5 years, correlating with age at ALL diagnosis (1-9 years 1·0% (N=769), 10-15 years 9·9% (N=1025), ≥16 years 20·0% (N=262), p<0·0001) and gender (≥10 years, female 15·7% (N=525) versus male 9·3% (N=762), p=0·0010). For patients ≥10 years old with a rapid response to induction therapy, the use of alternate-week dexamethasone during delayed intensification phases significantly reduced osteonecrosis incidence compared with continuous dexamethasone (8·7±2·1% (N=420) versus 17·0±2·9% (N=403), p=0·0005), especially those ≥16 years (11·3±5·3% (N=84) versus 37·5±11·1% (N=79), p=0·0003; females 17·2±8·1% (N=32) versus 43·9±14·1% (N=23), p=0·050; males 7·7±5·9% (N=53) versus 34·6±11·6% (N=56), p=0·0014). Interpretation Alternate-week dexamethasone during delayed intensification phases effectively reduces osteonecrosis risk in children and adolescents receiving intensified therapy for high-risk ALL.

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Section: Discussionmentioning

confidence: 99%

Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial

Mattano

Devidas

Nachman

et al. 2012

The Lancet Oncology

151

171

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“…Previous literature reviews were excluded. Specific musculoskeletal effects, including low BMD (5), osteonecrosis (6), slipped capital femoral epiphyses (7), limb salvage and amputation related late effects (10), oncogenic rickets (8), and hormone-related growth complications after cranial radiation (9) were excluded because comprehensive reviews have been published. Primary outcomes were defined as the occurrence of musculoskeletal complications at least 2 years after completion of cancer therapy.…”

Section: Methodsmentioning

confidence: 99%

“…Late musculoskeletal effects such as low bone mineral density (BMD) (5), osteonecrosis (6), slipped capital femoral epiphyses (7), oncogenic rickets (8), hormone-related growth disturbances (9), and limb salvage and amputation-related outcomes (10), have been comprehensively reviewed. However, the current state of knowledge about other, equally important, musculoskeletal late effects has not been systematically evaluated.…”

Section: Introductionmentioning

confidence: 99%

A Systematic Review of Selected Musculoskeletal Late Effects in Survivors of Childhood Cancer

Gawade¹,

Hudson²,

Kaste³

et al. 2015

CPR

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Survivors of childhood cancer are at risk for treatment-related musculoskeletal late effects. Early detection and orthopedic intervention can help ameliorate musculoskeletal late effects and prevent subsequent complications. This systematic review summarizes the literature describing associations between cancer, its treatment, and musculoskeletal late effects. We searched PubMed and Web of Science for English language articles published between January 1970 and December 2012. The search was limited to investigations with at least 15 participants and conducted at least 2 years after completion of therapy for childhood, adolescent, or young adult cancer. Some late skeletal effects, including low bone mineral density, osteonecrosis, slipped capital femoral epiphyses, oncogenic rickets, and hormone-related growth disturbances have been previously reviewed and were excluded, as were outcomes following amputation and limb-salvage procedures. Of 2347 references identified, 30 met inclusion criteria and were retained. An additional 54 studies that met inclusion criteria were found in reference lists of retained studies. Of 84 studies, 60 focused on associations between radiotherapy, six between chemotherapy, and 18 between surgery and musculoskeletal late effects. We found that younger age, higher radiation dosage, and asymmetric or partial bone radiation volume influences the effects of radiation on the musculoskeletal system. Methotrexate and vincristine are associated with long-term muscular strength and flexibility deficits. Laminectomy and chest wall resection are associated with spinal malalignment, and enucleation is associated with orbital deformities among survivors. Radiotherapy, chemotherapy, and surgery are associated with musculoskeletal late effects independently and additively. Associations are additionally influenced by host and treatment characteristics.

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“…There was no attempt to differentiate between early and chronic osteonecrotic lesions based on signal intensity. Lesions that showed bone edema only without the typical rim for osteonecrosis (giving an appearance of decreased signal intensity with poorly defined margins on T1-weighted imaging) were excluded from the definition of osteonecrosis, as they can be seen with multiple other bone conditions, including bone marrow contusion, ischemia, and microfractures [14,20,21]. Rather, such lesions were called patchy according to a previously published definition [21] and were reported separately.…”

Section: Methodsmentioning

confidence: 99%