Sue C. Kaste

Treating Childhood Acute Lymphoblastic Leukemia without Cranial Irradiation

BACKGROUND Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. METHODS We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. RESULTS The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection. CONCLUSIONS With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.)

Image Gently: Ten Steps You Can Take to Optimize Image Quality and Lower CT Dose for Pediatric Patients

AJR:194, April 2010 This article suggests 10 steps that radiologists and radiologic technologists, with the assistance of their medical physicist, can take to obtain good quality CT images while properly managing radiation dose for children undergoing CT. The first six steps ideally should be completed before performing any CT on a pediatric patient. The final four steps address the unique consideration that should be given for each scanned patient.

The 'Image Gently' campaign: increasing CT radiation dose awareness through a national education and awareness program

ALARA (As Low As Reasonably Achievable) has been a guiding principle for pediatric radiologists for decades. The Society for Pediatric Radiology (SPR) has long been a leader in promoting safety in radiology practice in children. However, the ALARA principle has taken on new meaning in the past several years as the number of CT scans in children has skyrocketed. For example, it is estimated that since the 1980s when CT was beginning its ascendancy there has been up to an 800% increase. CT scans in children provide great benefit in patient care when used appropriately. However, increased use requires a team approach to ensure that only indicated exams are performed and at the Pediatr Radiol (2008) 38:265–269 DOI 10.1007/s00247-007-0743-3

Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute lymphoblastic leukemia.

Osteonecrosis is a severe glucocorticoid-induced complication of acute lymphoblastic leukemia treatment. We prospectively screened children (n = 364) with magnetic resonance imaging of hips and knees, regardless of symptoms; the cumulative incidence of any (grade 1-4) versus symptomatic (grade 2-4) osteonecrosis was 71.8% versus 17.6%, respectively. We investigated whether age, race, sex, acute lymphoblastic leukemia treatment arm, body mass, serum lipids, albumin and cortisol levels, dexamethasone pharmacokinetics, and genome-wide germline genetic polymorphisms were associated with symptomatic osteonecrosis. Age more than 10 years (odds ratio, = 4.85; 95% confidence interval, 2.5-9.2; P = .00001) and more intensive treatment (odds ratio = 2.5; 95% confidence interval, 1.2-4.9; P = .011) were risk factors and included as covariates in all analyses. Lower albumin (P = .05) and elevated cholesterol (P = .02) associated with symptomatic osteonecrosis, and severe (grade 3 or 4) osteonecrosis was linked to poor dexamethasone clearance (P = .0005). Adjusting for clinical features, polymorphisms of ACP1 (eg, rs12714403, P = 1.9 × 10(-6), odds ratio = 5.6; 95% confidence interval, 2.7-11.3), which regulates lipid levels and osteoblast differentiation, were associated with risk of osteonecrosis as well as with lower albumin and higher cholesterol. Overall, older age, lower albumin, higher lipid levels, and dexamethasone exposure were associated with osteonecrosis and may be linked by inherited genomic variation.

Bone mineral decrements in survivors of childhood acute lymphoblastic leukemia: frequency of occurrence and risk factors for their development

We assessed the clinical and treatment factors that predispose survivors of childhood acute lymphoblastic leukemia (ALL) to low bone mineral density (BMD). Using quantitative computed tomography, we determined the frequency of low BMD (defined as >1.645 standard deviations (SD) below the mean) in leukemia survivors treated with multiagent chemotherapy including prednisone and antimetabolite. All participants had completed therapy at least 4 years earlier, remained in continuous complete remission, and had no second malignancies. We statistically correlated BMD results with patient characteristics and treatment histories. Among 141 survivors (median age, 15.9 years; median time after diagnosis, 11.5 years), median BMD z score was −0.78 SD (range, −3.23 to 3.61 SDs). Thirty participants (21%; 95% confidence interval, 15% to 29%) had abnormally low BMD, a proportion significantly (P < 0.0001) greater than the expected 5% in normal populations. Risk factors for BMD decrements included male sex (P = 0.038), Caucasian race (P < 0.0001), and cranial irradiation (P = 0.0087). BMD inversely correlated with cranial irradiation dose. BMD z scores of patients who received higher doses of antimetabolites were lower than those of other patients. Childhood ALL survivors are at risk to have low BMD, especially males, Caucasians, and those who received cranial irradiation.

Bone Mineral Density Deficits in Survivors of Childhood Cancer: Long-term Follow-up Guidelines and Review of the Literature

The development of curative therapy for most pediatric malignancies has produced a growing population of childhood cancer survivors who are at increased risk for a variety of health problems resulting from their cancer or its treatment. Because of the fact that many treatment-related sequelae may not become clinically apparent until the survivor attains maturity or begins to age, the ability of primary care providers to anticipate late effects of treatment is essential for providing timely interventions that prevent or correct these sequelae and their adverse effects on quality of life. Altered bone metabolism during treatment for childhood cancer may interfere with attainment of peak bone mass, potentially predisposing to premature onset of and more severe complications related to osteopenia and osteoporosis. Bone mineral deficits have been reported after treatment for a variety of pediatric malignancies and represent morbidity that can be reduced or prevented through lifestyle changes and attention to other common cancer-related sequelae such as hypogonadism. The Childrens Oncology Group long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers provide risk-based surveillance recommendations that are based on expert opinion and review of the scientific literature for potential late effects of pediatric cancer therapy including osteopenia. This review summarizes the existing literature that has defined characteristics of cancer survivors at risk for bone mineral deficits and contributed to the surveillance and counseling recommendations outlined in the Childrens Oncology group long-term follow-up guidelines.

Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog–Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032

PURPOSE Two phase II studies assessed the efficacy of vismodegib, a sonic hedgehog (SHH) pathway inhibitor that binds smoothened (SMO), in pediatric and adult recurrent medulloblastoma (MB). PATIENTS AND METHODS Adult patients enrolled onto PBTC-025B and pediatric patients enrolled onto PBTC-032 were treated with vismodegib (150 to 300 mg/d). Protocol-defined response, which had to be sustained for 8 weeks, was confirmed by central neuroimaging review. Molecular tests to identify patterns of response and insensitivity were performed when tissue was available. RESULTS A total of 31 patients were enrolled onto PBTC-025B, and 12 were enrolled onto PBTC-032. Three patients in PBTC-025B and one in PBTC-032, all with SHH-subgroup MB (SHH-MB), exhibited protocol-defined responses. Progression-free survival (PFS) was longer in those with SHH-MB than in those with non-SHH-MB, and prolonged disease stabilization occurred in 41% of patient cases of SHH-MB. Among those with SHH-MB, loss of heterozygosity of PTCH1 was associated with prolonged PFS, and diffuse staining of P53 was associated with reduced PFS. Whole-exome sequencing identified mutations in SHH genes downstream from SMO in four of four tissue samples from nonresponders and upstream of SMO in two of four patients with favorable responses. CONCLUSION Vismodegib exhibits activity against adult recurrent SHH-MB but not against recurrent non-SHH-MB. Inadequate accrual of pediatric patients precluded conclusions in this population. Molecular analyses support the hypothesis that SMO inhibitor activity depends on the genomic aberrations within the tumor. Such inhibitors should be advanced in SHH-MB studies; however, molecular and genomic work remains imperative to identify target populations that will truly benefit.

Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation

Summary:Our purpose was to evaluate frequency and severity of bone mineral decrements and frequency of osteonecrosis in survivors of pediatric allogeneic bone marrow transplantation (alloBMT). We retrospectively reviewed demographic information, treatment, magnetic resonance (MR) imaging studies (hips and knees), and bone mineral density (BMD) studies of 48 patients as measured by quantitative computed tomography (QCT). In all, 24 patients were male; 37 were Caucasian. Median age at alloBMT was 10.3 years (1.6–20.4 years). Of the 48 patients, 43 underwent QCT. Median time between alloBMT and imaging was 5.1 years (1.0–10.2 years). Median BMD Z-score was −0.89 (−4.06 to 3.05). BMD Z-score tended to be associated with female sex (P=0.0559) but not with age at BMT, race, primary diagnosis, time from alloBMT, T-cell depletion of graft, total-body irradiation, or acute/chronic graft-versus-host disease (GVHD). MR showed osteonecrosis in 19 of 43 (44%). We found no associations between osteonecrosis and sex, race, diagnosis, age at BMT, history of GVHD, time from BMT, or T-cell depletion. Seven patients (15%) had MR changes of osteonecrosis and BMD Z-scores of less than –1 s.d. We conclude that pediatric alloBMT survivors have decreased BMD and are at risk of osteonecrosis. They should be monitored to assure early intervention that may ameliorate adverse outcomes.

Physical performance limitations in the Childhood Cancer Survivor Study cohort.

Physical performance limitations are one of the potential long-term consequences following diagnosis and treatment for childhood cancer. The purpose of this review is to describe the risk factors for and the participation restrictions that result from physical performance limitations among childhood cancer survivors who participated in the Childhood Cancer Survivor Study (CCSS). Articles previously published from the CCSS cohort related to physical performance limitations were reviewed and the results summarized. Our review showed that physical performance limitations are prevalent among childhood cancer survivors and may increase as they age. Host-based risk factors for physical disability include an original diagnosis of bone tumor, brain tumor, or Hodgkins disease; female sex; and an income less than

Magnetic resonance imaging detection of avascular necrosis of the bone in children receiving intensive prednisone therapy for acute lymphoblastic leukemia or non-Hodgkin lymphoma

20,000 per year. Treatment-based risk factors include radiation and treatment with a combination of alkylating agents and anthracyclines. Musculoskeletal, neurologic, cardiac, pulmonary, sensory, and endocrine organ system dysfunction also increase the risk of developing a physical performance limitation. In summary, monitoring of physical performance limitations in an aging cohort of childhood cancer survivors is important and will help determine the impact of physical performance limitations on morbidity, mortality, and caregiver burden. In addition, in developing restorative and preventive interventions for childhood cancer survivors, we must take into account the special needs of survivors with physical disability to optimize their health and enhance participation in daily living activities.