Cognitive Sequelae in Children Treated for Acute Lymphoblastic Leukemia With Dexamethasone or Prednisone

Waber, Deborah P.; Carpentieri, Sarah C.; Klar, Neil; Silverman, Lewis B.; Schwenn, Molly; Hurwitz, Craig A.; Mullenix, Phyllis J.; Tarbell, Nancy J.; Sallan, Stephen E.

doi:10.1097/00043426-200005000-00004

Cited by 145 publications

(84 citation statements)

References 32 publications

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“…Dexamethasone also may have an affect on neurocognitive development, particularly as it relates to tasks with a memory demand. 8 Furthermore, the cumulative incidence of bony morbidity, especially fractures, was found to be significantly higher in patients receiving dexamethasone compared with those receiving prednisone. 9 Reilly et al examined the effect of postinduction steroid therapy on energy intake, which leads to the excess weight gain observed in children who complete therapy for ALL.…”

Section: Discussionmentioning

confidence: 94%

Dexamethasone‐associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin

Belgaumi

Al-Bakrah²,

Al-Mahr³

et al. 2003

Cancer

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BACKGROUNDThe goals of the current study were to examine the incidence and severity of toxicity resulting from dexamethasone and prednisone during induction therapy for children with precursor B‐cell acute lymphoblastic leukemia (ALL) and to determine whether the addition of daunomycin affected toxicity.METHODSMedical records of patients with precursor B‐cell ALL from January 1996 through June 2000 were reviewed retrospectively for toxicity during the 4‐week induction phase and the 2 weeks after the induction phase.RESULTSOne hundred seventy‐six patients age < 14 years were diagnosed with precursor B‐cell ALL from January 1996 through June 2000. Of the 156 evaluable patients, 106 were treated with prednisone and 50 with dexamethasone. Fifty‐two patients received steroids, L‐asparaginase, and vincristine, whereas 104 high‐risk patients received daunomycin in addition to these 3 agents. The incidence of gastritis was significantly higher among patients receiving dexamethasone (P = 0.01); incidence rates of hyperglycemia, hypertension, and myopathy were similar for all treatment groups. Dexamethasone led to more weight gain than did prednisone (+11.9% vs. +5.4%; P = 0.002). Serious infections were observed in 27 (25.5%) and 18 (36%) patients receiving prednisone and dexamethasone, respectively (P ≤ 0.2). Five patients, four of whom received prednisone and one of whom received dexamethasone, died of infection. The addition of daunomycin to treatment regimens increased overall toxicity (P < 0.01). When daunomycin was included in treatment regimens, toxicity was greater among patients receiving dexamethasone; in contrast, when daunomycin was not included, toxicity was equal for both treatment groups. Regardless of daunomycin use, there was no difference in the incidence of serious infection between the two groups. ALL treatment was not compromised by steroid‐related toxicity in either group.CONCLUSIONSThe addition of daunomycin led to a much larger increase in dexamethasone‐related toxicity compared with the increase in prednisone‐related toxicity. Although the use of daunomycin enhanced dexamethasone‐related toxicity, this enhancement did not result in a higher mortality rate or the alteration of planned ALL therapy. Cancer 2003;97:2898–903. © 2003 American Cancer Society.DOI 10.1002/cncr.11390

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Section: Discussionmentioning

confidence: 94%

Dexamethasone‐associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin

Belgaumi

Al-Bakrah²,

Al-Mahr³

et al. 2003

Cancer

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“…Waber et al compared patients treated on previous ALL regimens that included different corticosteroid preparations. 26 They found greater neurocognitive impairment in the dexamethasone group for memory, reading comprehension, and mathematics. However, the dexamethasone group also had lower participation rates, younger age at diagnosis, higher rates of cranial radiation (70% vs 50% in the prednisone group), and lower educational attainment by the parents.…”

Section: Discussionmentioning

confidence: 96%

A comparison of neurocognitive functioning in children previously randomized to dexamethasone or prednisone in the treatment of childhood acute lymphoblastic leukemia

Kadan‐Lottick

Brouwers

Breiger

et al. 2009

Blood

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In previous clinical trials of childhood acute lymphoblastic leukemia (ALL), dexamethasone resulted in higher event-free survival rates than prednisone, presumably due to greater central nervous system penetration. Dexamethasone's association with long-term neurocognitive toxicity is unknown. In this multisite study, we measured neurocognitive functioning in 92 children with standard-risk ALL, 1 to 9.99 years at diagnosis, at a mean of 9.8 years after randomization to prednisone (n ‫؍‬ 41) or dexamethasone (n ‫؍‬ 51) on Children's Cancer Group (CCG) 1922. No significant overall differences in mean neurocognitive and academic performance scores were found between the prednisone and dexamethasone groups after adjusting for age, sex, and time since diagnosis. The exception was that patients receiving dexamethasone scored one-third of a standard deviation worse on word reading (98.8 ؎ 1.7 vs 104.9 ؎ 1.8; P ‫؍‬ .02). There were no group differences in the distribution of test scores or the parents' report of neurologic complications, psychotropic drug use, and special education. Further analyses suggested for the dexamethasone group, older age of diagnosis was associated with worse neurocognitive functioning; for the prednisone group, younger age at diagnosis was associated with worse functioning. In conclusion, our study did not demonstrate any meaningful differences in long-term cognitive functioning of childhood ALL patients based on corticosteroid randomization. This study is registered with http://www. clinicaltrials.gov under NCT00085176. IntroductionCorticosteroids have long been recognized as an important component of therapy for childhood acute lymphoblastic leukemia (ALL). More recently, randomized control clinical trials have established a therapeutic benefit of dexamethasone over prednisone. In the Children's Cancer Group (CCG) 1922 trial of 1060 patients, Bostrom et al concluded that patients randomized to dexamethasone had a 6-year event-free survival of 85% plus or minus 2% compared with 77% plus or minus 2% for those randomized to prednisone (P ϭ .002). 1 Patients randomized to dexamethasone had a lower rate of both isolated central nervous system (CNS) and bone marrow relapse. These results are consistent with those found by most other cooperative groups. 2-4 Dexamethasone's therapeutic advantage is thought to be, in part, due to its better CNS penetration. 5 The recently completed CCG 1991 trial reported event-free survival rates approaching 90% and overall survival rates of approximately 95% for standard-risk ALL patients, who were nonrandomly treated with dexamethasone. 6 Therefore, the effect of different therapies on future quality of life has increasingly been considered as a critical factor in the selection of optimal treatment. Multiple previous studies of long-term survivors of childhood ALL, even those who did not receive cranial radiation, 7-12 have identified deficits in neurocognitive function that might impair quality of life. Among others, investigators have consistently identified di...

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“…We have reported that the substitution of dexamethasone for prednisone during remission induction was associated with a high incidence of septic episodes and deaths 25 and that post-remission dexamethasone may be associated with more severe neurocognitive late effects. 26 The Children's Cancer Group recently reported a 9.3% incidence of osteonecrosis in patients treated with both prednisone and dexamethasone, with higher rates noted in patients receiving higher cumulative doses of dexamethasone. 27 The incidence of osteonecrosis was not prospectively collected on Protocol 91-01, although we observed that 16% of patients experienced a fracture.…”

Section: Discussionmentioning

confidence: 99%

Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01

Silverman

2001

Blood

736

660

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The Dana-Farber Cancer Institute (DFCI) acute lymphoblastic leukemia (ALL) Consortium Protocol 91-01 was designed to improve the outcome of children with newly diagnosed ALL while minimizing toxicity. Compared with prior protocols, post-remission therapy was intensified by substituting dexamethasone for prednisone and prolonging the asparaginase intensification from 20 to 30 weeks. Between 1991 and 1995, 377 patients (age, 0-18 years) were enrolled; 137 patients were considered standard risk (SR), and 240 patients were high risk (HR). Following a 5.0-year median follow-up, the estimated 5-year event-free survival (EFS) ؎ SE for all patients was 83% ؎ 2%, which is superior to prior DFCI ALL Consortium protocols conducted between 1981 and 1991 (P ‫؍‬ .03). There was no significant difference in 5-year EFS based upon risk group (87% ؎ 3% for SR and 81% ؎ 3% for HR, P ‫؍‬ .24). Age at diagnosis was a statistically significant prognostic factor (P ‫؍‬ .03), with inferior outcomes observed in infants and children 9 years or older. Patients who tolerated 25 or fewer weeks of asparaginase had a significantly worse outcome than those who received at least 26 weeks of asparaginase (P < .01, both univariate and multivariate). Older children (at least 9 years of age) were significantly more likely to have tolerated 25 or fewer weeks of asparaginase (P < .01). Treatment on Protocol 91-01 significantly improved the outcome of children with ALL, perhaps due to the prolonged asparaginase intensification and/or the use of dexamethasone. The inferior outcome of older children may be due, in part, to increased intolerance of intensive therapy.

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Cognitive Sequelae in Children Treated for Acute Lymphoblastic Leukemia With Dexamethasone or Prednisone

Abstract: The findings of this preliminary study are consistent with the hypothesis that dexamethasone therapy can increase risk for neurocognitive late effects in children treated for ALL and indicate that further investigation of this question is warranted.

Cited by 145 publications

References 32 publications

Dexamethasone‐associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin

Dexamethasone‐associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin

A comparison of neurocognitive functioning in children previously randomized to dexamethasone or prednisone in the treatment of childhood acute lymphoblastic leukemia

Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01

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