Conventional Compared with Individualized Chemotherapy for Childhood Acute Lymphoblastic Leukemia

Evans, William E.; Relling, Mary V.; Rodman, John H.; Crom, William R.; Boyett, James M.; Pui, Ching‐Hon

doi:10.1056/nejm199802193380803

Cited by 438 publications

(267 citation statements)

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“…5,29 Accordingly, some studies have shown that the cure rates or the degree of toxicity can be influenced by individualization of therapy based on the patients drug disposition or previous degree of toxicity. 41,42 One of the important challenges for hematologists is to improve the cure rates for adolescents and young adults to the level of that obtained for children. 43 To examine the biology of their leukemias, their pharmacology, treatment efficacy and pattern of side effects, as well as their compliance to therapy, adult hematologists in Denmark, Norway and Sweden will treat young adults between 18 and 45 years of age according to the NOPHO ALL-2008 protocol.…”

Section: Discussionmentioning

confidence: 99%

Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

et al. 2009

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Analysis of 2668 children with acute lymphoblastic leukemia (ALL) treated in two successive Nordic clinical trials (Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL-92 and ALL-2000) showed that 75% of all patients are cured by first-line therapy, and 83% are long-term survivors. Improvements in systemic and intrathecal chemotherapy have reduced the use of central nervous system (CNS) irradiation to o10% of the patients and provided a 5-year risk of isolated CNS relapse of 2.6%. Improved risk stratification and chemotherapy have eliminated the previous independent prognostic significance of gender, CNS leukemia and translocation t(1;19)(q23;p13), whereas the post-induction level of minimal residual disease (MRD) has emerged as a new risk grouping feature. Infant leukemia, high leukocyte count, T-lineage immunophenotype, translocation t(4;11)(q21;q23) and hypodiploidy persist to be associated with lower cure rates. To reduce the overall toxicity of the treatment, including the risk of therapy-related second malignant neoplasms, the current NOPHO ALL-2008 protocol does not include CNS irradiation in first remission, the dose of 6-mercaptopurine is reduced for patients with low thiopurine methyltransferase activity, and the protocol restricts the use of hematopoietic stem cell transplantation in first remission to patients without morphological remission after induction therapy or with high levels of MRD after 3 months of therapy.

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Section: Discussionmentioning

confidence: 99%

Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

et al. 2009

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“…British Journal of Cancer (2001) and reduce drug toxicity (Evans et al, 1998). However, with the exceptions of carboplatin, methotrexate and 6-mercaptopurine, no rational approach to individualized dosing of drugs administered to paediatric patients has emerged, and surface area is the most commonly used parameter with which to adjust doses for the wide range of body sizes encountered in paediatric oncology.…”

Section: Discussionmentioning

confidence: 99%

“…Drug clearance, and by definition systemic exposure, also shows wide inter-and intra-patient variation (Crom et al, 1987). This wide variation in systemic exposure may have a significant effect on disease response (Evans et al, 1998) and drug toxicity. Since changes in these physiological and pharmacokinetic parameters were thought to correlate most closely with Body Surface Area (BSA), it is this measurement which forms the basis of dose normalization with respect to variations in age, body size and body composition.…”

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confidence: 99%

Body surface area estimation in children using weight alone: application in paediatric oncology

et al. 2001

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The majority of chemotherapy regimens and trials specify doses of cytotoxic drugs normalized to body surface area. Estimation of BSA in paediatric patients is particularly problematic, as conventional nomograms require accurate determination of both height and weight. The chemotherapy standards group of the UKCCSG (United Kingdom Children's Cancer Study Group) has evaluated a method for calculation of body surface area (BSA) estimation, based solely on patient weight. In comparison with BSA estimations using 2 commonly used methods, which require both weight and height measurements, deviation in the estimate of BSA was less than 10%. This method may be extended to the dosing of chemotherapeutic agents in infants of body weight less than 10 kg, with appropriate recommendations for dose modification. Until better correlates of drug clearance, such as GFR for carboplatin, are identified BSA is used to standardize doses for most chemotherapeutic agents. The formula presented here provides a more robust and reliable method of calculation of BSA from weight alone. Although this approach has been shown to be equivalent to other currently used methods, care should be taken extending this calculation of BSA to children less than 10 kg, to obese patients and to those with cachexia. © 2001 Cancer Research Campaign http://www.bjcancer.com

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“…etoposide [40,41]. TDM-guided dose individualization of methotrexate, teniposide and cytarabine has permitted the safe increase drug exposure in children with leukaemia [42], resulting in a signi®cant improvement in disease free as compared with conventional therapy.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and pharmacodynamics of oral etoposide

Toffoli

Corona

Sorio

et al. 2001

Brit J Clinical Pharma

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Aims To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours.Methods A prospective, open label, cross‐over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P‐Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints.Results Mean clearance was 1.14 l h−1 (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r2 = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l−1 h; CV 64%; range 0.4–9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l−1 h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l−1 h) than in patients with stable (2.1 mg l−1 h) or progressive disease (2.3 mg l−1 h) (P = 0.01).Conclusions Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.

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Conventional Compared with Individualized Chemotherapy for Childhood Acute Lymphoblastic Leukemia

Abstract: Adjusting the dose of methotrexate to account for the patient's ability to clear the drug can improve the outcome in children with B-lineage acute lymphoblastic leukemia.

Cited by 438 publications

References 20 publications

Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia

Body surface area estimation in children using weight alone: application in paediatric oncology

Population pharmacokinetics and pharmacodynamics of oral etoposide

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