Protracted Etoposide During Induction Therapy for High Risk Neuroblastoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Protracted Etoposide During Induction Therapy for High Risk Neuroblastoma (NCT00578864), a non-randomized phase 2 study. The primary outcome is Response Rate Associated With Two Cycles of Cisplatin With Protracted Oral Etoposide When Administered as Up-front Window Therapy to Previously Untreated Children With High Risk Neuroblastoma Tumors..

2. Clinical Question

3. Trial Design

This was a Phase II study with a parallel model and non-randomized allocation. Masking was listed as none. The registry record lists an enrollment of 13 and a completed status. The listed start was 2007-03 and primary completion was 2009-07. These are registry dates, not evidence about when particular participants were treated or assessed.

The two treatment approaches described were protracted oral etoposide with IV cisplatin and IV bolus etoposide with IV cisplatin. The protracted approach was described for induction cycles 1, 2 and 4; the bolus approach was described for patients not eligible for the experimental arm. The record also says that all patients would receive other listed induction agents, but the arm descriptions are incomplete. The complete treatment sequence and any deviations from it are not reported in the registry record.

The safety groups list 7 participants at risk in the protracted-etoposide group and 6 in the bolus-etoposide group. These group counts are not evidence of randomized assignment. The record explicitly identifies the study as non-randomized and notes that the arms are not a like-for-like control comparison. Differences in eligibility or other participant characteristics could therefore complicate comparisons between them.

The record identifies several secondary outcomes, including overall survival, event-free survival and surgery after the second induction cycle. It lists 5 outcome measures and 2 analyses, but does not report the statistical plan, analysis populations, or results for these secondary outcomes in the registry record for this analysis.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Response Rate Associated With Two Cycles of Cisplatin With Protracted Oral Etoposide When Administered as Up-front Window Therapy to Previously Untreated Children With High Risk Neuroblastoma Tumors., measured over 2 months.

The primary endpoint is a participant count for response associated with two cycles of cisplatin and protracted oral etoposide, administered as up-front window therapy to previously untreated children with high-risk neuroblastoma. The response threshold is partial response or better, and the timeframe is 2 months.

A response endpoint gives a clinically interpretable summary of whether tumors meet a specified response category after treatment. Defining a threshold such as partial response or better makes the outcome categorical: each participant either meets the criterion or does not, according to the endpoint definition. A count can then be used to describe how many participants met that criterion. This is a general explanation of response endpoints; the registry record does not provide the detailed assessment rules used to assign response categories.

For this study, the endpoint definition and timeframe are recorded, but its result is not. The registry record does not report the number of participants with partial response or better, the denominator used for the primary analysis, a response proportion, or an uncertainty interval. As a result, the endpoint can be described, but the observed response frequency and its precision cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

General: interpreting a binary endpoint. A response outcome defined as partial response or better is categorical. Each participant is classified according to whether the response criterion was met. The natural descriptive result is a count, accompanied by the number assessed. A proportion can also describe the fraction meeting the criterion, but the registry record does not report the primary response count or its analysis denominator. No response proportion can therefore be interpreted from the available record.

General: uncertainty around a count or proportion. A confidence interval expresses the range of estimates reasonably compatible with the observed data under a statistical method and its assumptions. It helps show how precisely an outcome has been estimated; it does not guarantee that the true value lies within a particular interval. No confidence interval for the primary response outcome is reported in the registry record, and without the outcome count and denominator there is no posted estimate whose precision can be assessed.

General: non-randomized treatment groups. Random assignment is one way to make treatment groups comparable on average, including with respect to factors that were not measured. This study is recorded as non-randomized, and the registry record says the arms are not a like-for-like control comparison. Participants in the two arms may have differed in eligibility or other characteristics. A difference in an outcome between such groups would not, by itself, identify a treatment effect. The registry entries do not describe an adjustment strategy or provide participant characteristics that would allow an adjusted comparison to be evaluated.

General: why the endpoint timeframe matters. An endpoint is interpreted in relation to when it is measured. The primary response timeframe is 2 months, associated with two cycles of treatment. This defines the timing attached to the registry endpoint, but the record does not describe how assessment visits were scheduled, how response was evaluated, or how participants without an assessment at that time were handled.

General: missing outcome information. A missing result in a registry record is not the same thing as a participant having no response, nor does it show that the outcome was not measured. It means the result is not reported in the record being summarized. The primary response count, analysis denominator, handling of missing assessments, and statistical method are not reported in the registry record. No assumption about missing outcomes should be substituted for those absent details.

General: multiplicity. When a study evaluates multiple outcomes or makes multiple statistical comparisons, the chance of at least one apparently unusual result can change unless the analysis accounts for that multiplicity. The registry record lists 5 outcome measures and 2 analyses, and it names several secondary outcomes. It does not report whether any multiplicity adjustment was planned or used, which analyses correspond to the listed outcomes, or how primary and secondary findings were prioritized. The number of listed outcomes alone does not establish that a particular adjustment was necessary or applied.

General: safety counts. Counts of participants with an event describe how many people in a group were recorded as affected; they do not describe event severity in full, timing, recurrence, or exposure-adjusted rates. The safety record lists 0 serious adverse events among 7 participants at risk in the protracted-etoposide group and 0 among 6 in the bolus-etoposide group. It also lists other adverse events for all participants at risk in each group. The registry record does not provide detailed event terms for these other events or describe the period of safety follow-up.

The sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. The effect to detect is expressed as a fraction of the observed effect. Such assumptions concern hypothetical planning, not observed trial results or observed power. No numerical planning illustration is included in the registry record for this analysis, and the registry record does not report the trial's own sample-size justification or statistical analysis plan.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Phase II Window With Protracted Etoposide", "Phase II Window With Bolus Etoposide")
n      <- c(7, 6)
events <- c(1, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Phase II Window With Protracted Etoposide  7  1  14.3  0.4  57.9  2.6  51.3  3.2  52.7
ARM  Phase II Window With Bolus Etoposide  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 5 outcome measures and 2 analyses, with overall survival, event-free survival and surgery after the second induction cycle among the secondary outcomes. It does not report how the analyses were mapped to the outcomes, which outcomes were formally designated as primary or secondary in the analysis plan, or whether any adjustment for multiple comparisons was planned or used. A multiplicity procedure should not be inferred from the number of outcomes listed.

The primary endpoint is named and has a timeframe of 2 months, but the record does not state the primary response count, analysis denominator, or statistical method. It also does not describe the analysis population, such as whether all enrolled participants were included or whether eligibility for an analysis depended on treatment received or outcome assessment. These details are not reported in the registry record.

How missing response assessments were handled is also not reported in the registry record. There is no stated method for excluding, classifying, or otherwise accounting for participants without an evaluable assessment. This prevents assessment of whether missing outcome data could affect the reported response result; in any case, the response result itself is not reported.

The registry record does not report interim analyses, stopping rules, a sample-size justification, or a full statistical analysis plan. Their absence from the record should not be interpreted as evidence that none were considered or performed. The appropriate conclusion is limited to what is documented: the record identifies outcomes and counts of analyses, but does not provide enough methodological detail to assess multiplicity control, missing-data handling, or analysis-population choices.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent non-serious adverse event terms

The registry record separates serious adverse events from other adverse events. In the group titled Phase II Window With Protracted Etoposide, 0 of 7 participants at risk were listed as affected by a serious adverse event, while 7 of 7 were listed under other adverse events. In the group titled Phase II Window With Bolus Etoposide, the corresponding counts were 0 of 6 for serious adverse events and 6 of 6 for other adverse events.

These figures are participant counts, not counts of individual event episodes. They do not show how many events each participant experienced, when events occurred, or how long participants were followed. The record does not list serious-event terms, and it does not provide detailed terms for the other adverse events. The death fields are not reported in the registry record.

The safety counts are descriptive. Because allocation was non-randomized and the arms are not a like-for-like control comparison, the counts do not establish that either schedule caused more or fewer adverse events. The reported zeros mean that no participants were recorded in the serious-event affected count for these groups; they do not establish that serious risks are absent or that risks are the same across groups.

13. What the Result Does, and Does Not, Mean

The registry record documents a Phase II study of protracted etoposide during induction therapy for high-risk neuroblastoma. It specifies a primary question about partial response or better after two cycles of cisplatin with protracted oral etoposide, within 2 months. It also describes a bolus-etoposide approach for participants not eligible for the protracted approach and records safety counts for both groups.

What the record does not provide is the numerical result for the primary response endpoint. There is no reported count of participants meeting the response threshold, no analysis denominator, and no uncertainty interval. The treatment question can be understood, but the primary outcome cannot be quantified from the registry record.

The design also limits interpretation of comparisons between treatment groups. Allocation was non-randomized, and the record states that the arms are not a like-for-like control comparison. Any difference between groups would therefore require careful interpretation and could not, on this information alone, be attributed to the treatment schedule.

The serious adverse event counts are 0 of 7 in the protracted-etoposide group and 0 of 6 in the bolus-etoposide group. Other adverse events are recorded for 7 of 7 and 6 of 6 participants, respectively. These are descriptive registry counts, not proof of equivalence or evidence that a treatment is safe or unsafe. The record lacks detailed event descriptions and safety follow-up information.

The registry record also identifies survival and surgery outcomes, but numerical findings for those outcomes are not reported in the registry record for this analysis. The study status is completed, but completion does not fill in outcome information that is absent from the record. Conclusions should remain limited to the stated design, endpoint definition, and posted safety counts.

14. Why This Trial Matters Statistically

This trial raises a useful statistical distinction between a well-defined research question and a reported result. The registry record describes a response threshold, treatment context, and timeframe: partial response or better after two cycles, assessed within 2 months. Yet the primary response count and denominator are not reported. A clearly specified endpoint is important, but it cannot establish the observed response or its precision in the absence of outcome data.

The non-randomized design is also central to interpretation. The record describes two treatment approaches but explicitly cautions that the arms are not a like-for-like control comparison. This highlights why treatment-group contrasts depend not only on outcome counts but also on how participants entered each group and whether relevant differences can be addressed analytically. The registry entries do not report the information needed to evaluate that issue further.

The safety counts illustrate another statistical point: a zero count in a small group is a descriptive observation, not proof that an event cannot occur or that risks are equivalent between groups. Counts need context about denominators, event definitions, follow-up, and uncertainty. The record provides group denominators and affected counts but not detailed event terms or safety follow-up.

Finally, the record lists multiple outcomes and analyses without documenting multiplicity methods, missing-data handling, or a complete analysis plan. These omissions do not establish that such methods were absent from the study, but they limit what can be assessed from the registry record. The statistical importance of the trial therefore lies partly in recognizing the boundary between what is documented and what remains unreported.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The principal limitation for interpreting efficacy is that the registry record does not report the primary response result. Although it defines the response threshold and timeframe, it gives no number of participants with partial response or better, no primary analysis denominator, and no interval describing uncertainty. The primary outcome therefore cannot be quantitatively evaluated from the record.

The non-randomized allocation and the record's warning that the arms are not a like-for-like control comparison limit any interpretation of treatment-group differences. Baseline characteristics, reasons for assignment, and adjustment methods are not reported in the registry entries. The treatment descriptions are also incomplete, so the full regimen and actual treatment received cannot be reconstructed.

Important analysis details are not reported in the registry record, including the statistical methods, analysis populations, missing-outcome handling, multiplicity procedures, and interim analyses. The record lists 5 outcome measures and 2 analyses but does not explain how these were organized or analyzed. It also does not report results for the listed survival and surgery outcomes in the registry record for this analysis.

Safety interpretation is limited by absent event descriptions and follow-up information. Serious-event counts are reported, but serious terms are not listed, other adverse-event terms are not posted in the record, and deaths are not reported. These limitations restrict conclusions to the counts and design details actually documented.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Protracted Etoposide During Induction Therapy for High Risk Neuroblastoma — NCT00578864.
• Registry record last updated 2020-03-27; status last verified 2020-03.
• Results first posted 2012-11-06.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry record describes NCT00578864, a completed Phase II study of protracted etoposide during induction therapy for high-risk neuroblastoma. It lists enrollment of 13, a parallel model, non-randomized allocation, and no masking. The primary endpoint is a participant count for partial response or better after two cycles of cisplatin with protracted oral etoposide, with a timeframe of 2 months.

The primary response result is not reported in the registry record. Safety counts list 0 serious adverse events among 7 participants at risk in the protracted-etoposide group and 0 among 6 in the bolus-etoposide group; other adverse events are listed for all participants at risk in both groups. The record names overall survival, event-free survival, and surgery after the second induction cycle as secondary outcomes, but their numerical results are not reported in the registry record for this analysis. Non-randomized allocation limits causal interpretation of any comparison between the treatment groups.