Vincristine, Dactinomycin, and Cyclophosphamide With or Without Radiation Therapy in Treating Patients With Newly Diagnosed Low-Risk Rhabdomyosarcoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Vincristine, Dactinomycin, and Cyclophosphamide With or Without Radiation Therapy in Treating Patients With Newly Diagnosed Low-Risk Rhabdomyosarcoma (NCT00075582), a non-randomized phase 3 study. The primary outcome is Percentage of Patients With Low-risk Rhabdomyosarcoma in Subset 1 Failure Free at 5 Years Following Study Entry.

2. Clinical Question

In general, this type of endpoint combines several events that represent failure of the defined failure-free state. It describes how long participants remain free from the first listed event, rather than measuring only one type of recurrence or progression. The registry's stated question is therefore broader than a question about tumor response alone.

The study record states that it was not yet known which regimen was more effective. That statement describes the question motivating the trial; it is not a result. The registered design and the outcome information available in the record do not establish whether one regimen produced a better outcome, nor do they support a causal comparison between the arms.

3. Trial Design

This was a phase III, parallel, non-randomized study sponsored by the Children's Oncology Group. The registry reports an enrollment of 390 and a completed status. The recorded study start is 2004-09-04, and the primary completion date is 2012-08-13. These registry entries describe the study's design and timing; they do not supply an outcome estimate.

The two named groups are Regimen I (chemotherapy, radiotherapy) and Regimen II (chemotherapy, radiotherapy, surgery). The registry lists conventional surgery, dactinomycin, cyclophosphamide, vincristine sulfate, and radiation therapy among the interventions. The descriptions indicate chemotherapy and radiation therapy in the regimens, but the available schedule text ends before the full treatment details are given. A complete account of each regimen's dosing, duration, and treatment differences is not reported in the registry record.

Non-randomized allocation is central to interpreting the comparison. In a randomized study, allocation by chance is intended to reduce systematic differences between groups. In a non-randomized study, treatment assignment may be associated with patient or clinical characteristics. The registry does not describe how participants were allocated, the reasons for assignment, or methods used to address differences between groups. Without those details, observed group differences would not by themselves demonstrate that treatment caused the differences.

The registry lists masking as none. It does not report further details about who knew treatment assignment or whether outcome assessment used any safeguards against knowledge of treatment. The planned sample-size justification, allocation procedure, interim analyses, and detailed statistical plan are not reported in the registry record. The enrollment figure is not evidence that the study achieved a particular statistical precision or power.

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:

Analysis population for the primary outcome, as defined in the registry: Patients found not to meet the eligibility requirements are by group policy not followed for adverse events or outcome.

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 Percentage of Patients With Low-risk Rhabdomyosarcoma in Subset 1 Failure Free at 5 Years Following Study Entry, measured over From enrollment up to 5 years.

The primary endpoint is the estimated percentage of patients in Subset 1 who were failure-free at five years following study entry. The registry defines failure-free survival as time to relapse, progression, a second malignancy, or death, whichever occurs first, and gives the timeframe as enrollment up to five years. It identifies the estimate as a Kaplan–Meier estimate and specifies a 95% confidence interval.

In general, a time-to-event endpoint incorporates both whether an event occurred and when it occurred. Kaplan–Meier estimation is commonly used to estimate the probability of remaining event-free over time when participants have different follow-up durations. Participants whose follow-up ends before an event is observed can contribute information up to the time they were last followed; this is generally called censoring. The registry does not report the number or timing of censored observations or the follow-up distribution for this outcome.

Combining relapse, progression, second malignancy, and death into one endpoint gives a broad measure of time until the first defined failure. It does not separately quantify each component, and an overall estimate cannot show which component contributed most. The registry record does not report the five-year estimate, its confidence interval, or component-specific outcome results. The endpoint is therefore defined, but its observed result and precision cannot be assessed from the information reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help explain what the registered endpoint could measure and what the available record can support. These are general explanations; the specific analysis details are not reported unless stated below.

What does failure-free survival measure?

Failure-free survival is a time-to-event measure. The event is the first occurrence of any item in the endpoint definition: relapse, progression, a second malignancy, or death. The time origin is study entry, and the registry gives the outcome timeframe as enrollment up to five years. A participant who experiences more than one listed event is counted at the time of the first event for this composite endpoint. Separate results for the individual event types are not reported in the registry record.

Time-to-event analysis is useful when follow-up length varies across participants or when some participants have not experienced the event by the end of their observed follow-up. In general, observations without an event during observed follow-up are censored at their last known event-free time. Censoring allows the information available up to that time to contribute to the analysis; it does not mean that a participant is known to remain event-free afterward. The registry does not report censoring counts, reasons, or assumptions used in the analysis.

What does Kaplan–Meier estimation mean?

The registry identifies the primary endpoint as a Kaplan–Meier estimate. In general, this method estimates the probability of remaining event-free over time while accounting for censoring. The estimate at a chosen time point, such as the registered five-year point, is a summary of the estimated event-free probability through that time. It is not simply the proportion of all enrolled participants who had no event, because follow-up duration and censoring affect the calculation.

Kaplan–Meier estimates rely on assumptions, including that censoring is not related to a participant's underlying event risk in a way that distorts the estimate. The registry does not report diagnostic checks or detail the assumptions used. The exact analysis population, handling of participants who did not meet eligibility requirements, and approach to missing outcome information are not reported in the registry record.

How should a confidence interval be read?

The registry specifies a 95% confidence interval for the endpoint estimate. In general, a confidence interval presents a range of values compatible with the observed data under the method and assumptions used. It communicates uncertainty about the estimate rather than certainty about each participant's outcome. Its width is informative about precision, but it does not account for every possible source of bias, such as systematic differences between non-randomized groups.

The estimated value and confidence limits themselves are not reported in the registry record. Consequently, the interval's width and the precision of the five-year estimate cannot be evaluated. No confidence interval for a contrast between regimens is reported either.

Why does allocation matter?

Allocation was non-randomized, and the registry identifies the arms as not being a like-for-like control comparison. In general, random allocation helps balance measured and unmeasured characteristics across treatment groups, on average. Non-randomized assignment does not provide the same protection. Patient characteristics, disease features, clinical decisions, or other factors may differ between groups and may also relate to outcome.

Statistical adjustment can sometimes address measured differences, but it cannot guarantee that all confounding has been removed. The registry does not report the allocation process, baseline comparisons, adjusted analyses, or the covariates considered. It is therefore not possible to determine whether or how group differences were addressed. A comparison of group outcomes, even if one were reported, would require careful qualification.

What can sample-size planning show?

In general, sample-size planning illustrates the amount of information a study might need under specified assumptions. The record describes a planning illustration using a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not observed outcomes, and the resulting sample-size illustrations are not reported in the registry record.

A planning calculation does not demonstrate that an effect was observed, and it is not observed power. Power calculations depend on assumptions about the effect and variability or event process. If those assumptions differ from what occurs, the achieved precision can differ from planning expectations. The registry does not report its own design justification or enough outcome information to assess achieved power or precision.

In general, over-dispersion means that observed variability exceeds what a simpler statistical model assumes. When present, ignoring it can make uncertainty estimates too small. The registry does not report a count model for the primary endpoint or any indication that over-dispersion was assessed, so this concept should not be taken as a description of the analysis used in this trial.

What is missing from the analysis description?

The registry reports no analyses for the outcome measures. The detailed statistical plan, approach to censoring, analysis population, handling of missing data, covariate adjustments, and any interim analyses are not reported in the registry record. It also does not report a statistical comparison of the two groups. These absences prevent assessment of the methods beyond the endpoint and confidence-interval descriptions that are explicitly registered.

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("Regimen I (Chemotherapy, Radiotherapy)", "Regimen II (Chemotherapy, Radiotherapy, Surgery)")
n      <- c(269, 69)
events <- c(234, 46)
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  Regimen I (Chemotherapy, Radiotherapy)  269  234  87.0  82.4  90.8  82.4  90.5  82.4  90.5
ARM  Regimen II (Chemotherapy, Radiotherapy, Surgery)  69  46  66.7  54.3  77.6  54.9  76.6  54.9  76.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and secondary outcomes that include cumulative incidence of patients receiving reduced radiation doses, delayed surgical procedures, and cumulative incidence in Group III patients who received reduced radiotherapy dose. It reports six outcome measures, but no analyses. The detailed hierarchy among outcomes, any prespecified testing order, and any adjustment for multiple comparisons are not reported in the registry record.

In general, testing several outcomes or examining multiple subgroups can increase the chance of finding an apparently notable result by chance. Multiplicity procedures can control that risk, but the record does not state whether any were planned or used. Since no analyses are reported, the statistical significance of primary or secondary outcomes cannot be evaluated.

The primary outcome population is described as patients in Subset 1, and the registry notes that patients found not to meet eligibility requirements were not followed for adverse events or outcome by group policy. The definition of Subset 1, the number of participants meeting eligibility criteria, and the number included in each outcome analysis are not reported in the registry record. Nor are the number of missing outcome observations, reasons for missingness, or any imputation or sensitivity analysis.

In general, missing follow-up can affect time-to-event estimates if participants who cannot be followed differ in their future event risk from those who remain observed. Censoring methods address incomplete observation under assumptions; they do not automatically eliminate bias. The registry does not report enough detail to assess those assumptions or the handling of missing data.

The statistical analysis populations, including whether analyses followed an intention-to-treat, per-protocol, or other approach, are not reported in the registry record. These limitations apply to both the outcome estimates and any potential comparison between the non-randomized arms.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neutrophil count decreased (1.4%), white blood cell decreased (0.4%).

The registry reports serious adverse events for Regimen I among 272 participants at risk, with 1 affected participant, and for Regimen II among 70 participants at risk, also with 1 affected participant. The listed top serious-event terms are “Neutrophil count decreased” at 1.4% and “White blood cell decreased” at 0.4%. The registry does not identify those term percentages by treatment group in the information, so they should not be assigned to a particular arm.

For other adverse events, the registry lists 74 affected participants among 272 at risk in Regimen I and 27 among 70 at risk in Regimen II. These are participant counts, not a formal comparison. The registry's outcome meaning describes a percentage of participants with an event, but these counts alone do not give an exposure-adjusted rate or account for differences between groups. Death counts are not reported in the registry record.

In general, adverse-event counts depend on who was observed, how long they were observed, and how events were defined and collected. Here, allocation was non-randomized, and the group sizes differ. The figures describe reported events in the registered groups; they cannot establish that a regimen caused more or fewer events or that one was safer. A fuller safety assessment would require details not reported in the registry record, including event timing, follow-up duration, and analysis methods.

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

The registry record establishes that the study was completed, describes two non-randomized treatment groups, and defines a primary five-year failure-free survival endpoint. It also lists secondary outcomes and adverse-event counts. These details clarify what the study was intended to examine and provide limited descriptive safety information.

It does not report the primary endpoint estimate or its 95% confidence interval. Therefore, the failure-free survival result and its precision cannot be stated. No outcome analysis or statistical comparison between groups is reported. The record cannot establish whether outcomes differed, how large any difference was, or whether a difference was statistically distinguishable from chance.

Even if outcome estimates were available, non-randomized allocation would require caution. Differences between groups might be associated with differences in participant characteristics or treatment assignment rather than treatment itself. The allocation process and methods for addressing such differences are not reported in the registry record. The registered information therefore does not support a causal conclusion about the relative effects of the regimens.

The endpoint is a composite: its first event can be relapse, progression, second malignancy, or death. An overall endpoint estimate would not show the separate contribution of each component. The registry does not report component-specific results, and those outcomes should not be inferred from the endpoint definition.

The safety figures are counts of participants with reported events, not proof of a comparative safety difference. The groups were not randomized, have different numbers at risk, and lack reported exposure-adjusted analyses. The numbers also do not supply missing information about event timing or follow-up.

In short, the record supports a description of the trial's design, outcome definition, and selected adverse-event data. It does not provide the efficacy results or analysis details needed to judge treatment effects, precision, or comparative safety. The absence of reported results in the registry should not be interpreted as evidence that no events or differences occurred.

14. Why This Trial Matters Statistically

This trial is statistically notable for the contrast between a clearly defined time-to-event endpoint and the limited outcome information reported in the registry. The endpoint specifies a time origin, a five-year timeframe, a Kaplan–Meier estimate, and a 95% confidence interval. Those features identify the intended summary, but without the estimate and interval, the amount and precision of the observed outcome remain unknown.

The non-randomized parallel design is also important. It illustrates why treatment-arm comparisons require more than reading two outcome summaries side by side. In general, randomization is one way to reduce systematic group differences; non-randomized allocation leaves open the possibility that factors related to treatment choice also relate to outcome. The registry explicitly warns that the groups are not a like-for-like control comparison, and does not report enough detail to assess confounding adjustment.

The composite endpoint raises a further interpretive issue: a single failure-free survival summary brings several different events together. That may be useful as a broad endpoint, but it cannot show the separate pattern of relapse, progression, second malignancy, and death. Component results are not reported in the registry record.

Finally, the safety summaries demonstrate why counts need context. Group sizes differ, event exposure time is not described, and allocation was non-randomized. The reported counts are descriptive and do not substitute for a comparative safety analysis. Together, these features make the record a useful example of the distinction between a registered question, a design, and a reported statistical result.

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 is that the registry record does not report the primary endpoint result, its confidence interval, or any outcome analyses. The effect, precision, and statistical significance of the primary endpoint cannot be assessed. The record also does not report a statistical comparison between the treatment groups.

Allocation was non-randomized, and the groups are identified as not being a like-for-like control comparison. The registry does not describe how treatment was assigned, why participants entered each group, or what methods were used to address potential group differences. These omissions limit any interpretation of a between-group contrast.

The primary outcome refers to Subset 1, but the definition of that subset and its analysis population are not reported. The registry notes that patients found not to meet eligibility requirements were not followed for adverse events or outcome by group policy; it does not give the number affected or the consequences for analysis. Missing-data handling, censoring details, follow-up completeness, and sensitivity analyses are also not reported.

The available treatment descriptions are incomplete, so the full schedules and differences between regimens cannot be established from the registry record. In addition, the composite endpoint combines several event types, while separate component results are not reported. The adverse-event data lack a reported formal comparison, exposure-adjusted rates, and death counts. These limitations constrain interpretation of both the efficacy question and the descriptive safety figures.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Vincristine, Dactinomycin, and Cyclophosphamide With or Without Radiation Therapy in Treating Patients With Newly Diagnosed Low-Risk Rhabdomyosarcoma — NCT00075582.
• Registry record last updated 2021-11-19; status last verified 2021-11.
• Results first posted 2014-04-11.
• 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 describes a completed phase III, parallel, non-randomized study sponsored by the Children's Oncology Group, with enrollment of 390. Its primary outcome is the Kaplan–Meier estimate of the percentage of patients in Subset 1 who were failure-free at five years, with failure defined as relapse, progression, second malignancy, or death, whichever occurs first.

The named groups are Regimen I and Regimen II, and the listed interventions include chemotherapy, radiation therapy, and surgery. The primary result, confidence interval, and statistical analyses are not reported in the registry record. Serious and other adverse-event counts are reported by group, but they do not constitute a randomized comparative safety analysis. Because allocation was non-randomized and the registry warns that the groups are not like-for-like, causal comparisons are not supported by the registered information.