Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer

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Abstract

One of the most important adverse effects of anthracyclines is cardiotoxicity. A well-informed decision on the use of anthracyclines in the treatment of childhood cancers should be based on evidence regarding both antitumour efficacy and cardiotoxicity. This review is the second update of a previously published Cochrane review.

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Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial.

N Goulden, Chris Mitchell, Rachel Wade … (2013)

Minimal residual disease (MRD) is the most sensitive and specific predictor of relapse risk in children with acute lymphoblastic leukaemia (ALL) during remission. We assessed whether treatment intensity could be adjusted for children and young adults according to MRD risk stratification. Between Oct 1, 2003 and June 30, 2011, consecutive children and young adults (aged 1-25 years) with ALL from the UK and Ireland were recruited. Eligible patients were categorised into clinical standard, intermediate, and high risk groups on the basis of a combination of National Cancer Institute (NCI) criteria, cytogenetics, and early response to induction therapy, which was assessed by bone marrow blast counts taken at days 8 (NCI high-risk patients) and 15 (NCI standard-risk patients) after induction began. Clinical standard-risk and intermediate-risk patients were assessed for MRD. Those classified as MRD low risk (undetectable MRD at the end of induction [day 29] or detectable MRD at day 29 that became undetectable by week 11) were randomly assigned to receive one or two delayed intensification courses. Patients had received induction, consolidation, and interim maintenance therapy before they began delayed intensification. Delayed intensification consisted of pegylated asparaginase on day 4; vincristine, dexamethasone (alternate weeks), and doxorubicin for 3 weeks; and 4 weeks of cyclophosphamide and cytarabine. Computer randomisation was done with stratification by MRD result and balancing for sex, age, and white blood cell count at diagnosis by method of minimisation. Patients, clinicians, and data analysts were not masked to treatment allocation. The primary outcome was event-free survival (EFS), which was defined as time to relapse, secondary tumour, or death. Our aim was to rule out a 7% reduction in EFS in the group given one delayed intensification course relative to that given two delayed intensification courses. Analyses were by intention to treat. This trial is registered, number ISRCTN07355119. Of 3207 patients registered in the trial overall, 521 MRD low-risk patients were randomly assigned to receive one (n=260) or two (n=261) delayed intensification courses. Median follow-up of these patients was 57 months (IQR 42-72). We recorded no significant difference in EFS between the group given one delayed intensification (94·4% at 5 years, 95% CI 91·1-97·7) and that given two delayed intensifications (95·5%, 92·8-98·2; unadjusted odds ratio 1·00, 95% CI 0·43-2·31; two-sided p=0·99). The difference in 5-year EFS between the two groups was 1·1% (95% CI -5·6 to 2·5). 11 patients (actuarial relapse at 5 years 5·6%, 95% CI 2·3-8·9) given one delayed intensification and six (2·4%, 0·2-4·6) given two delayed intensifications relapsed (p=0·23). Three patients (1·2%, 0-2·6) given two delayed intensifications died of treatment-related causes compared with none in the group given one delayed intensification (p=0·08). We recorded no significant difference between groups for serious adverse events and grade 3 or 4 toxic effects; however, the second delayed intensification course was associated with one (<1%) treatment-related death, and 74 episodes of grade 3 or 4 toxic effects in 45 patients (17%). Treatment reduction is feasible for children and young adults with ALL who are predicted to have a low risk of relapse on the basis of rapid clearance of MRD by the end of induction therapy. Medical Research Council and Leukaemia and Lymphoma Research. Copyright © 2013 Elsevier Ltd. All rights reserved.

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Statistical considerations in the intent-to-treat principle.

John M. Lachin (2000)

This paper describes some of the statistical considerations in the intent-to-treat design and analysis of clinical trials. The pivotal property of a clinical trial is the assignment of treatments to patients at random. Randomization alone, however, is not sufficient to provide an unbiased comparison of therapies. An additional requirement is that the set of patients contributing to an analysis provides an unbiased assessment of treatment effects, or that any missing data are ignorable. A sufficient condition to provide an unbiased comparison is to obtain complete data on all randomized subjects. This can be achieved by an intent-to-treat design wherein all patients are followed until death or the end of the trial, or until the outcome event is reached in a time-to-event trial, irrespective of whether the patient is still receiving or complying with the assigned treatment. The properties of this strategy are contrasted with those of an efficacy subset analysis in which patients and observable patient data are excluded from the analysis on the basis of information obtained postrandomization. I describe the potential bias that can be introduced by such postrandomization exclusions and the pursuant effects on type I error probabilities. Especially in a large study, the inflation in type I error probability can be severe, 0.50 or higher, even when the null hypothesis is true. Standard statistical methods for the analysis of censored or incomplete observations all require the assumption of missing at random to some degree, and none of these methods adjust for the potential bias introduced by post hoc subset selection. Nor is such adjustment possible unless one posits a model that relates the missing observations to other observed information for each subject-models that are inherently untestable. Further, the subset selection bias is confounded with the subset-specific treatment effect, and the two components are not identifiable without additional untestable assumptions. Methods for sensitivity analysis to assess the impact of bias in the efficacy subset analysis are described. It is generally believed that the efficacy subset analysis has greater power than the intent-to-treat analysis. However, even when the efficacy subset analysis is assumed to be unbiased, or have a true type I error probability equal to the desired level alpha, situations are described where the intent-to-treat analysis in fact has greater power than the efficacy subset analysis. The intent-to-treat design, wherein all possible patients continue to be followed, is especially powerful when an effective treatment arrests progression of disease during its administration. Thus, a patient benefits long after the patient becomes noncompliant or the treatment is terminated. In such cases, a landmark analysis using the observations from the last patient evaluation is likely to prove more powerful than life-table or longitudinal analyses. Examples are described.

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Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95.

Anja Möricke, Alfred Reiter, Martin Zimmermann … (2008)

The trial ALL-BFM 95 for treatment of childhood acute lymphoblastic leukemia was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in poor-risk groups by treatment intensification. These aims were pursued through a stratification strategy using white blood cell count, age, immunophenotype, treatment response, and unfavorable genetic aberrations providing an excellent discrimination of risk groups. Estimated 6-year event-free survival (6y-pEFS) for all 2169 patients was 79.6% (+/- 0.9%). The large standard-risk (SR) group (35% of patients) achieved an excellent 6y-EFS of 89.5% (+/- 1.1%) despite significant reduction of anthracyclines. In the medium-risk (MR) group (53% of patients), 6y-pEFS was 79.7% (+/- 1.2%); no improvement was accomplished by the randomized use of additional intermediate-dose cytarabine after consolidation. Omission of preventive cranial irradiation in non-T-ALL MR patients was possible without significant reduction of EFS, although the incidence of central nervous system relapses increased. In the high-risk (HR) group (12% of patients), intensification of consolidation/reinduction treatment led to considerable improvement over the previous ALL-BFM trials yielding a 6y-pEFS of 49.2% (+/- 3.2%). Compared without previous trial ALL-BFM 90, consistently favorable results in non-HR patients were achieved with significant treatment reduction in the majority of these patients.