Proton Radiation Therapy (RT) for the Treatment of Pediatric Rhabdomyosarcoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Proton Radiation Therapy (RT) for the Treatment of Pediatric Rhabdomyosarcoma (NCT00592592), a na na study. The primary outcome is Cumulative Incidence (Estimated Percent of Participants) With Grade 3 or Higher Toxicity in Follow-up.

2. Clinical Question

The study’s stated purpose is to examine whether proton radiation, rather than photon radiation, can reduce radiation-treatment side effects in pediatric rhabdomyosarcoma. The scientific motivation described in the registry is that photon beams pass through healthy tissue before and after reaching a tumor, whereas proton beams stop after reaching the tumor. That rationale motivates the comparison, but it does not itself establish a difference in toxicity.

The registered primary endpoint is a single-group estimate: cumulative incidence of participants who experience a grade 3, 4, or 5 toxicity after completing radiation therapy. Late toxicity is to be assessed yearly for at least five years, with the specified estimate at five years. The registry record does not report the numerical estimate or its confidence interval. Because no photon group is listed, the posted record does not directly quantify a proton-versus-photon difference for this endpoint.

3. Trial Design

This is a completed, single-group study of proton beam radiation for rhabdomyosarcoma. The registry lists Massachusetts General Hospital as sponsor, enrollment of 115, and phase as NA. The study start is recorded as 2004-10 and primary completion as 2010-08. Allocation is listed as NA, masking as none, and the model as single group. The intervention and the sole arm description are both Proton Beam Radiation.

The registry record frames the study around the possible reduction of radiation side effects compared with photon beam radiation. Photon radiation is described as the standard type for treating most rhabdomyosarcoma and many other cancers. However, the design details list only a proton-radiation group. There is therefore no concurrent photon arm in the registered design to serve as a direct control. The stated comparison is a study rationale, not a randomized or like-for-like contrast in the listed trial arms.

The primary outcome is late grade 3 or higher toxicity, assessed after radiation and estimated at five years from the start of radiation treatment. The endpoint description says late toxicities are scored yearly for at least five years and graded using CTCAE Version 3.0. Other registered outcomes concern acute toxicity by grade, dosimetric comparison, and local control. The registry indexes 4 outcome measures and 6 analyses, but does not report detailed analytic procedures for those outcomes.

The record gives an overall enrollment figure, but the primary endpoint result and its analysis population are not reported in the registry record. The participant count used for each outcome, losses during follow-up, and the handling of missing assessments are also not reported. The registry status is COMPLETED; that status indicates the study is recorded as completed, not that every planned endpoint result is available in the record.

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 Cumulative Incidence (Estimated Percent of Participants) With Grade 3 or Higher Toxicity in Follow-up, measured over 5 years from the start of radiation treatment.

The primary endpoint is the estimated cumulative incidence of participants with grade 3 or higher toxicity in follow-up. The endpoint definition includes grade 3, 4, or 5 toxicity occurring after completion of radiation therapy. Toxicities are to be graded according to CTCAE Version 3.0, with late toxicity scored yearly for at least five years. The reported time point is five years from the start of radiation treatment.

A cumulative-incidence estimate describes the occurrence of an event over a specified follow-up period, rather than only counting events at one isolated visit. General statistical context: follow-up measures are useful when participants may be observed for different lengths of time, because the timing of an event matters as well as whether it occurred. The exact method used to calculate this endpoint is not reported in the registry record.

The endpoint focuses on more severe toxicity, as defined by its grade threshold, and expresses the result as a percentage of patients with an associated 95% confidence interval. A confidence interval communicates uncertainty around an estimated event frequency; it is not a guarantee that the true value lies within a particular interval. The registry record does not report the primary estimate or interval, so the magnitude and precision of the five-year toxicity estimate cannot be assessed from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary endpoint as a cumulative incidence, expressed as an estimated percentage of participants with grade 3 or higher toxicity in follow-up, and gives a 95% confidence interval as the uncertainty measure. It does not state the numerical estimate, interval limits, or detailed calculation method. The distinction between an endpoint definition and a reported endpoint result matters: knowing what investigators planned to measure does not reveal the frequency observed in participants.

What does a cumulative-incidence measure describe?

General statistical explanation: cumulative incidence represents the probability or proportion of a defined population experiencing an event by a specified time, subject to the method and assumptions used. It uses the follow-up horizon as part of the outcome definition. In this trial, the specified horizon is five years from the start of radiation treatment. The endpoint description also says late toxicity is scored yearly for at least five years. The precise time-to-event methods, including how incomplete follow-up was handled, are not reported in the registry record.

General statistical explanation: when participants can experience events that prevent or change the chance of observing the event of interest, the analysis may need to account for those competing events. The registry lists 28 deaths for the intervention group, but the information available does not say whether or how deaths were treated in calculating the primary cumulative incidence. It would therefore be inappropriate to infer the endpoint method from the word “cumulative incidence” alone.

How should the confidence interval be read?

General statistical explanation: a confidence interval presents a range of values compatible with the data and the statistical model used, at the stated confidence level. It is a measure of precision around an estimate, not a measure of clinical importance and not proof that a particular value is true. The primary endpoint specifies a 95% confidence interval, but its endpoints are not reported in the registry record. Without the interval, readers cannot judge how precisely the five-year estimate was determined.

The endpoint is a percentage and the registry’s outcome type is a percentage of participants with an event. This differs from a count of events when participants may have multiple events: an event frequency and a participant frequency do not necessarily represent the same quantity. The primary endpoint is framed around participants who experienced toxicity, not a total count of toxicity episodes. The record does not give the underlying numerator or denominator for that endpoint.

What do the planning assumptions mean?

The registry’s sample-size planning illustration is described as a hypothetical calculation based on the observed effect, not the trial’s original design. Its stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It describes detecting a stated fraction of the observed effect. The actual values for those planning illustrations are not reported in the registry record used for this analysis, and no resulting participant counts can be interpreted.

These assumptions do not describe the registered study design. This trial is listed as a single-group study with no allocation between two treatment arms. Thus, equal allocation between two arms belongs to the planning illustration, not to the trial’s enrollment or treatment assignment. A planning illustration is a way to express hypothetical sample-size requirements under selected assumptions; it is not evidence that the study had that size, and it is not observed power. The stated illustration does not supply the trial’s own sample-size justification, which is not reported in the registry record.

The planning description distinguishes event totals for time-to-event calculations using the Schoenfeld method from participant counts per arm for other calculations. General statistical explanation: event-based planning is used in some time-to-event settings because the information available for comparing event timing is related to the number of observed events. Participant-based planning instead expresses the required number of people in each group. The registry record does not provide enough detail to identify a planning result for the primary endpoint, and the single-group design should not be confused with the hypothetical two-arm assumptions.

More generally, normal approximations use a mathematical distribution to approximate the behavior of an estimator or test statistic. Their suitability depends on the outcome, sample information, and assumptions of the calculation. The registry’s planning description names a normal approximation, but does not report diagnostics or further details. No actual test statistic or p-value for the primary endpoint is reported.

The record lists 4 outcome measures and 6 analyses. Those counts indicate multiple registered measures and analyses, but do not specify which were primary or secondary tests in the final analysis, how each was conducted, or whether inferential adjustments were applied. The primary endpoint is clearly named; its result and detailed statistical analysis remain unreported. No additional model, covariate adjustment, interim analysis, or stopping procedure is described in the registry record.

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("Proton Beam Radiation")
n      <- c(114)
events <- c(12)
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  Proton Beam Radiation  114  12  10.5  5.6  17.7  6.1  17.5  6.2  17.5

11. Multiplicity, Missing Data and Analysis Populations

The registry indexes 4 outcome measures and 6 analyses. It names late grade 3 or higher toxicity as the primary endpoint and lists acute toxicity by grade, dosimetric comparison, and local control among the secondary outcomes. The record does not report which analyses correspond to each outcome, whether hypotheses were tested, or whether any adjustment for multiple comparisons was used. A multiplicity strategy is not reported in the registry record.

General statistical context: when several outcomes or analyses are examined, the chance of obtaining at least one apparently notable result can increase if each is interpreted independently. Adjustment methods, prespecified outcome hierarchies, or cautious descriptive interpretation can address different aspects of this issue. The available information does not establish that any particular approach was planned or used in this study. Since numerical outcome results are also not reported, multiplicity cannot be assessed from the posted findings.

The primary endpoint description specifies yearly scoring of late toxicities for at least five years and an estimate at five years from the start of radiation. The record does not report how many participants had complete follow-up, how missing visits were handled, whether follow-up varied, or whether participants were excluded from an analysis. The analysis population for the primary endpoint is not reported in the registry record. Enrollment of 115 should therefore not be assumed to equal the denominator for every endpoint.

The adverse-event summaries list 114 participants at risk, while the registry enrollment is 115. The reason for that difference is not reported. No explanation is given for missing adverse-event information or for the analysis population used for other outcomes. These reporting gaps limit assessment of possible selection or attrition effects and prevent reconstruction of the endpoint analyses.

12. Safety Results

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

Deaths

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: right eye blindness (0.9%), abdominal pain (0.9%), mood alteration- depression (0.9%), infection- other (thrush) (0.9%), infection- other (c diff) (0.9%).

For the Proton Beam Radiation group, the registry lists 114 participants at risk for serious adverse events, of whom 6 were affected. For other adverse events, 114 were at risk and 113 were affected. The record lists 28 deaths in the group. It does not report timing or causes of death in the information, or explain whether deaths were considered related to treatment.

The serious adverse-event terms listed with frequencies are Right eye blindness, Abdominal pain, Mood alteration- Depression, Infection- Other (Thrush), Infection- Other (C Diff), and Febrile Neutropenia; each is reported as 0.9%. These term-level frequencies are not a complete account of the clinical context, severity, timing, or attribution of each event. The registry record does not state whether terms were mutually exclusive or whether an individual could contribute to more than one term.

General statistical context: adverse-event listings describe events reported during a study and should not automatically be interpreted as events caused by the intervention. A serious-event count is also distinct from the primary late-toxicity endpoint, which is defined by grade and follow-up time. The registry does not provide enough information to connect these summaries to the primary endpoint or to estimate comparative safety against photon radiation.

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

The study is registered as an investigation of proton beam radiation in pediatric rhabdomyosarcoma, with a primary focus on the estimated cumulative incidence of grade 3 or higher toxicity at five years. The endpoint definition is specific about the toxicity grades, the post-radiation period, and the planned follow-up horizon. However, the numerical result and its 95% confidence interval are not reported in the registry record. The principal quantitative question therefore remains unanswered by the outcome information.

The record does report adverse-event counts for the proton group and a list of serious-event terms with frequencies. Those data describe the entries recorded for that group, but they do not provide a direct comparison with photon radiation, identify causal relationships, or replace the primary endpoint estimate. The record also includes deaths without enough detail to interpret their timing or causes.

The study’s stated rationale concerns a possible difference in healthy-tissue exposure between proton and photon beams. That is a rationale for asking a clinical question, not evidence of a clinical outcome difference. Because the registered design is single-group and lists no photon arm, outcomes in the proton group cannot by themselves establish what would have happened to comparable participants receiving photon radiation.

General statistical context: estimates are most informative when their population, outcome definition, follow-up period, and uncertainty are all clear. Here, the intended population and endpoint are described, but the primary estimate, interval, and analysis details are absent. No conclusion about the size or precision of late toxicity, local control, dosimetric comparison, or acute toxicity can be drawn from the information reported in this record.

Accordingly, the record supports a description of the study design, endpoint, and selected adverse-event summaries. It does not support a quantitative claim that proton radiation reduced toxicity compared with photon radiation, nor a claim that it did not. Those comparative conclusions would require an appropriate comparison and reported outcome results, neither of which is present in the registry information.

14. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between its clinical motivation and its registered design. The stated question concerns whether proton radiation can reduce side effects compared with photon radiation, yet the study is listed as single-group and includes only a proton-radiation arm. That structure can describe outcomes among treated participants, but it does not directly estimate the difference between proton and photon treatment.

The primary endpoint also illustrates why definitions and results must be read separately. The registry specifies a cumulative incidence of grade 3 or higher toxicity at five years and a 95% confidence interval. It describes yearly scoring of late toxicity for at least five years and identifies CTCAE Version 3.0 for grading. These details clarify the intended measure, but the absence of the estimate and interval means its frequency and precision cannot be evaluated.

The record further shows why the denominator should be checked for each outcome. Overall enrollment is 115, while the adverse-event summaries identify 114 participants at risk. The reason is not reported, and no primary-endpoint denominator is given. Without endpoint-specific analysis populations and missing-data details, readers cannot know whether each outcome includes all enrolled participants.

Finally, the record’s planning illustration is not a description of the trial’s actual design or a report of observed power. Its hypothetical equal-allocation assumptions differ from the single-group design. Distinguishing a planning calculation, a registered endpoint, an observed safety count, and a treatment comparison is essential to avoid attributing more evidential strength to the record than its reported data support.

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 primary limitation for interpretation is that the registry record does not report the numerical result for the primary five-year cumulative-incidence endpoint or its 95% confidence interval. Without those values, the estimate’s magnitude and precision cannot be evaluated. The record also does not give the underlying number of participants with the endpoint or the denominator used for the analysis.

The single-group design is a specific limitation for the comparative question motivating the study. Although the summary discusses proton radiation in relation to photon radiation, no photon arm is listed. The posted record therefore does not provide a concurrent treatment comparison or a direct estimate of relative toxicity.

Additional limitations include unreported details about endpoint analysis, missing follow-up, analysis populations, and the reason adverse-event summaries list 114 participants at risk while overall enrollment is 115. The registry does not state how deaths were handled in the primary cumulative-incidence analysis, despite listing 28 deaths for the group. Timing and causes of those deaths are not reported in the information used.

Although secondary outcomes include acute toxicity, dosimetric comparison, and local control, numerical results for them are not reported. The registry lists 4 outcome measures and 6 analyses but does not describe multiplicity procedures or link each analysis to its result. The registry entries available also do not report a sample-size justification for the trial, detailed statistical methods, or whether interim analyses were conducted. These omissions limit appraisal of both the planned analysis and the completeness of outcome reporting.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Proton Radiation Therapy (RT) for the Treatment of Pediatric Rhabdomyosarcoma — NCT00592592.
• Registry record last updated 2025-06-18; status last verified 2025-06.
• Results first posted 2025-06-18.
• 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

NCT00592592 is a completed, single-group study of proton beam radiation for pediatric rhabdomyosarcoma, sponsored by Massachusetts General Hospital. The registry lists enrollment of 115, phase NA, no masking, and no allocation. The study start is 2004-10 and primary completion is 2010-08.

The primary outcome is the estimated percentage of participants with grade 3 or higher toxicity at five years from the start of radiation treatment, with a 95% confidence interval. Late toxicities are described as scored yearly for at least five years and graded using CTCAE Version 3.0. The primary estimate and interval are not reported in the registry record.

Adverse-event summaries list 6 participants with serious events among 114 at risk, 113 with other events among 114 at risk, and 28 deaths. The record lists six serious-event terms, each at 0.9%. No photon comparison group is listed, so the record does not report a direct comparative estimate of proton versus photon radiation.