Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma (NCT00354835), a randomized phase 3 study. The primary outcome is Event Free Survival (EFS).

2. Clinical Question

3. Trial Design

NCT00354835 was a randomized phase III study sponsored by Children's Oncology Group. The registry lists the study as completed, with enrollment of 481. Its start date was 2006-12-26 and its primary completion date was 2014-12-31. These dates describe the registered study timeline; they do not by themselves establish the length of follow-up for every participant.

The design was parallel, with two treatment groups. One group received VAC chemotherapy, consisting of vincristine, dactinomycin and cyclophosphamide. The other received VAC alternating with VI, with VI consisting of vincristine and irinotecan. Both arms are described as involving radiation therapy. The registry records no masking. It does not report additional details about allocation concealment or how the randomization sequence was generated.

The trial’s stated focus was patients with newly diagnosed intermediate-risk rhabdomyosarcoma. The registry lists a wider set of condition terms, including adult and childhood rhabdomyosarcoma categories and soft-tissue sarcoma categories. A more complete description of eligibility criteria, the enrolled population’s baseline characteristics, and the numbers included in each primary-outcome analysis is not reported in the registry record.

The primary endpoint was four-year EFS probability. The registry also lists secondary outcomes involving overall survival, local failure, toxicity, comparisons with historical results, and PET SUVmax changes. A full statistical analysis plan, planned sample-size justification and details of any interim analyses are not reported in the registry record. The treatment schedules in the arm descriptions are truncated, so their complete timing and dosing are not reported in the registry record either.

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.

Before assignment: 481 excludes 33 ineligible cases (declared by the Study Chair) .

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 Event Free Survival (EFS), measured over 4 years.

Event-free survival (EFS) is the primary endpoint. The registry defines it as the probability of having no relapse, secondary malignancy or death after 4 year in the study. The recorded timeframe is 4 years, and the endpoint is expressed as a probability. This measure combines several kinds of events into one outcome: a participant experiences an EFS event if any of the listed events occurs.

In general, a time-to-event endpoint can reflect both whether an event occurs and when it occurs during follow-up. Reporting a probability at a specified time gives a time-specific summary, rather than a simple count of participants with an event at any point. The record does not report the method used to estimate EFS, how participants with incomplete follow-up were handled, or how the four-year time point was selected.

The posted arm-specific EFS probabilities are 0.625 for VAC and 0.587 for VAC alternating with VI. Their reported 95% confidence intervals are 0.557 to 0.693 and 0.518 to 0.657, respectively. These are estimates for each arm; they are not a confidence interval for the difference between arms. The registry does not report a direct comparison estimate or its confidence interval.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Randomization assigns participants to treatment groups by chance. In general, this helps make groups comparable with respect to measured and unmeasured characteristics at the start of a trial, although it does not ensure that every characteristic is balanced in a particular study. The registry identifies this study as randomized but does not report the sequence-generation or allocation-concealment procedures. It records no masking.

What do the arm estimates describe?

The primary outcome is a probability of EFS at 4 years. Each posted value is an estimate for one arm: 0.625 for VAC and 0.587 for VAC alternating with VI. In general, a probability estimate summarizes the outcome for the group under study; it is not a guarantee about what will happen to any particular participant. The record does not report how the estimates were calculated, so the exact statistical procedure cannot be assessed from the registry information.

How should the confidence intervals be read?

The registry gives a 95% confidence interval for each arm’s EFS estimate. For VAC, it is 0.557 to 0.693; for VAC alternating with VI, it is 0.518 to 0.657. In general, a confidence interval represents uncertainty in an estimate under a statistical method and its assumptions. It does not mean that 95% of participants fall within the interval, and it is not an interval for individual outcomes. Because these intervals are reported separately for the arms, they do not directly quantify uncertainty in the difference between the arms.

For a randomized comparison, the treatment contrast is usually the primary quantity for assessing how groups differ. It may be expressed using a difference, ratio or another measure chosen for the outcome and analysis plan. No comparative EFS estimate is reported in the registry record, and none can be recovered from the arm estimates without making additional analytical choices. The registry also does not report a p-value for this primary comparison.

Why does the event-free endpoint matter?

In general, a time-to-event outcome uses information about the time until an event, and can account for participants whose follow-up ends before an event is observed through methods that handle censoring. The EFS definition combines relapse, secondary malignancy and death. The registry does not report the number of events, the censoring approach, the follow-up distribution or the estimator used. It is therefore not possible to assess those features of the analysis from the registry record.

What is the role of the planning illustration?

The planning illustration is distinct from the trial’s own design justification. Its stated assumptions are a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect to detect defined as a stated fraction of the observed effect. For time-to-event outcomes, the illustration is based on a total number of events; for other outcomes, it is based on participants per arm. These are planning assumptions, not evidence that the trial was designed using those assumptions, and not observed power. The trial’s own sample-size justification is not reported in the registry record. The illustration’s resulting planning values are not part of the registry entries.

What information is needed to assess the analysis?

A fuller statistical appraisal would require the prespecified analysis method, population definition, handling of missing data, and any adjustments or sensitivity analyses. It would also require the planned treatment contrast and its uncertainty. Those details are not reported in the registry record. General statistical principles can explain why these items matter, but they cannot determine which methods this trial actually used.

In general, over-dispersion matters when observed variability exceeds what a statistical model assumes; ignoring it can make uncertainty estimates too small. The posted primary endpoint is a probability, but the registry entries do not identify an over-dispersion model or indicate that over-dispersion was assessed. No claim about its relevance to the trial’s primary analysis can be made from the recorded information.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple secondary outcomes, including overall survival, local failure, toxicity, PET SUVmax-related comparisons and historical comparisons. When several outcomes or analyses are examined, the chance of at least one apparently notable result can increase. In general, multiplicity procedures can address that issue, but they depend on the prespecified testing strategy and the intended interpretation of each outcome.

Whether the investigators planned a hierarchy, adjusted significance thresholds, or used another approach to multiplicity is not reported in the registry record. The record lists 15 outcome measures and 12 analyses. Those counts do not establish how many formal hypothesis tests were performed, whether all planned analyses were posted, or whether any adjustment was used.

The registry does not report the primary analysis population, the number of participants with evaluable EFS, or the method for handling missing outcome data and incomplete follow-up. For a time-to-event endpoint, follow-up ending before an event may be handled as censoring in an analysis, but the actual approach used in this trial is not reported in the registry record. The timing and completeness of outcome ascertainment are also not reported in the registry record.

Details about interim analyses, stopping rules, protocol deviations and sensitivity analyses are not reported in the registry record. These omissions limit assessment of how the posted results relate to the original analysis plan. The arm estimates can still be read as posted results, but they do not resolve these questions about multiplicity, missing data or analysis populations.

11. 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: nervous system disorders - other, specify (1.4%), death nos (0.9%), mucositis oral (0.9%), alanine aminotransferase increased (0.5%), anemia (0.5%).

The registry records serious adverse events among 4 of 222 participants at risk in the VAC group and 11 of 226 participants at risk in the VAC alternating with VI group. These are group counts; the registry entries do not state whether the counts represent participants with at least one serious adverse event or the total number of serious events. The registry lists no death counts for these groups, so deaths reported as serious adverse events are not reported in the registry record.

The listed serious adverse-event terms include Nervous system disorders - Other, specify at 1.4%, Death NOS at 0.9%, Mucositis oral at 0.9%, Alanine aminotransferase increased at 0.5%, Anemia at 0.5%, and Ascites at 0.5%. The registry entries do not identify these term percentages by treatment arm or provide their denominators. They should therefore be read as the posted term-level percentages, not as arm-specific comparisons.

The registry also records other adverse-event counts of 209 among 222 at risk in the VAC group and 213 among 226 at risk in the VAC alternating with VI group. The definitions and grading rules behind the “other” category are not reported in the registry record. These figures do not establish causation, comparative safety or the severity of every event. The registry’s broader toxicity outcomes include additional measures, but their results are not reported in the registry record.

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

The registry’s primary outcome estimates describe four-year EFS probability for participants assigned to each treatment group. The estimate is 0.625 for VAC and 0.587 for VAC alternating with VI. The 95% confidence intervals communicate uncertainty around each arm estimate: 0.557 to 0.693 for VAC and 0.518 to 0.657 for VAC alternating with VI.

These results do not provide a direct estimate of the difference between regimens. The registry record does not report the primary comparison’s effect estimate, confidence interval or p-value. A lower point estimate in one group is not, by itself, enough to establish a statistically supported or clinically meaningful difference. No conclusion that either regimen is more effective is justified by the arm-specific estimates alone.

The endpoint combines relapse, secondary malignancy and death. The reported probability does not show how much each event type contributed, and it does not describe other outcomes such as toxicity or overall survival. Although the registry lists several secondary outcome areas, their numerical results are not reported in the registry record in the registry record for this analysis.

In general, a confidence interval helps convey the precision of an estimate, but precision is not the same as clinical importance. The registry does not report a threshold for a meaningful difference or a prespecified interpretation framework. The trial’s detailed statistical plan, analysis population, missing-data approach and follow-up information are also not reported in the registry record.

The trial is recorded as randomized and parallel, with no masking. Those design features are relevant when considering potential bias, but they do not remove the need to examine outcome ascertainment, analysis choices and missing data. The posted results support a description of the two arm-specific EFS estimates and their uncertainty. They do not, on their own, settle a comparative question or support treatment advice.

13. Why This Trial Matters Statistically

This study illustrates the distinction between reporting an outcome in each randomized group and reporting the treatment contrast that answers a comparative question. Arm-level estimates are useful descriptions, but a reader assessing whether groups differ needs the contrast itself and its uncertainty. The registry reports EFS probabilities and separate confidence intervals, while a direct comparison estimate is not reported in the registry record.

The endpoint also raises an important general issue: a composite outcome may combine events that differ in nature and consequences. EFS here includes relapse, secondary malignancy and death. A single probability can summarize the composite, but it cannot show which component drives the result. Component-level results and their analysis are not reported in the registry record.

The trial’s many listed outcomes make multiplicity relevant to interpretation. In general, examining multiple endpoints or analyses can complicate the meaning of isolated findings unless the plan for prioritizing and interpreting them is clear. The registry does not report the multiplicity strategy or a full statistical analysis plan.

Finally, the distinction between an observed result and a planning illustration matters. Planning assumptions can help describe how a future study might be sized, but they are not observed trial outcomes or evidence of the trial’s original design rationale. The recorded assumptions are explicitly an illustration based on the observed effect; the trial’s own sample-size justification is not reported in the registry record. Together, these features make clear why outcome estimates, uncertainty, analysis methods and design rationale should be considered separately.

14. 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 primary results available for interpretation are arm-specific EFS probabilities with separate 95% confidence intervals. A direct comparison estimate, its uncertainty and a primary-comparison p-value are not reported in the registry record. The arm estimates therefore do not fully answer the randomized comparative question.

The registry does not report the statistical method used to estimate EFS, the event counts, the censoring rules, or the distribution and completeness of follow-up. The primary analysis population and the number included in the endpoint analysis are not reported in the registry record. Although arm sample sizes are listed, they should not be assumed to identify the number contributing to the EFS estimate.

The endpoint combines relapse, secondary malignancy and death. Component-specific primary-outcome results are not reported in the registry record, so the contribution of each event type cannot be assessed from the posted EFS probabilities. The registry lists other outcomes, including overall survival, local failure and toxicity, but their numerical results are not reported in the registry record in the registry entries.

The detailed treatment schedules in the arm descriptions are incomplete, and full eligibility criteria and baseline characteristics are not reported in the registry record. The registry also does not report allocation-concealment procedures, the analysis plan, multiplicity adjustments, interim analyses or the handling of missing data. These gaps do not change the posted estimates, but they restrict assessment of how robustly those estimates answer the intended question.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma — NCT00354835.
• Registry record last updated 2023-01-31; status last verified 2023-01.
• Results first posted 2017-07-25.
• 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.

18. Record Summary

NCT00354835 is a completed, randomized, phase III, parallel-group study sponsored by Children's Oncology Group. It enrolled 481 and compared VAC chemotherapy with VAC alternating with VI in newly diagnosed intermediate-risk rhabdomyosarcoma; both arms are described as involving radiation therapy. The registry records no masking.

The primary endpoint was four-year EFS probability, defined as no relapse, secondary malignancy or death after 4 year in the study. The posted estimates are 0.625 for VAC and 0.587 for VAC alternating with VI, with respective 95% confidence intervals of 0.557 to 0.693 and 0.518 to 0.657. A direct comparison estimate and key analysis details are not reported in the registry record.