Fractionated Stereotactic Radiosurgery for Large Brain Metastases: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fractionated Stereotactic Radiosurgery for Large Brain Metastases (NCT02054689), a na na study. The primary outcome is Number of Patients Experiencing DLT.

2. Clinical Question

3. Trial Design

The registry describes a completed, single-group radiation study with recorded enrollment of 20. Its official title identifies it as a phase I study, while the recorded phase is NA. The allocation field is NA and masking is listed as none. These entries do not establish a randomized design; the registry explicitly flags the dose groups as not being a like-for-like control comparison.

The intervention is fractionated stereotactic radiosurgery for large brain metastases. The arm description specifies 24 to 36 Gy in 3 fractions (8-12 Gy/fx), and the safety record lists groups at 24 Gy, 27 Gy, 30 Gy, 33 Gy, and 36 Gy. The registry does not explain how participants were assigned to these dose groups, or give a dose-escalation protocol. That design detail is not reported in the registry record.

The brief summary describes the treatment as splitting the total radiation dose into multiple smaller treatments and says the trial is for people with no prior whole brain radiation. The record lists the start date as 2013-07-16, the primary completion date as 2017-11-20, and status as completed. It does not report the number treated, follow-up completeness, or participant characteristics beyond the stated condition and prior-radiation criterion.

Secondary outcomes listed are Best Response, Local Control of Disease, Regional Intracranial Failure, and Functional Assessment of Cancer Therapy - Brain (FACT-Br). The record lists six outcome measures in total, but detailed outcome results and analyses are not reported. A single-group design can describe outcomes among participants receiving the intervention, but without a separate control group it cannot isolate treatment effects from other explanations for observed outcomes.

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

Analysis population for the primary outcome, as defined in the registry: All treated patients.

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 Number of Patients Experiencing DLT, measured over Up to 3 years.

The primary endpoint is the number of patients experiencing dose-limiting toxicity, with assessment extending up to 3 years. The stated population is all treated patients. The registry definition describes DLT as the maximum amount of Gy fractionated stereotactic radiosurgery delivered without significant toxicity. The endpoint is therefore intended to capture a dose-related toxicity limit, rather than a tumor response or a comparison of treatment effectiveness.

In general, toxicity limits are used in early treatment research to characterize tolerability and guide decisions about dose. Interpreting such an endpoint depends on a clear definition of significant toxicity, how events are attributed and assessed, and how the dose received relates to the event. The registry record does not provide detailed criteria for significant toxicity, the timing or grading rules for DLT, or the dose-assignment procedure.

The endpoint title names a count of patients experiencing DLT, but the posted record does not give the observed count, an estimate of its uncertainty, or a dose-specific primary endpoint result. It therefore does not permit a reader to determine how many treated participants met the DLT definition or how that count varied across dose groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation starts with identifying the question an outcome answers and the population to which it applies. Here, the primary outcome is a count of patients experiencing DLT, and the stated population is all treated patients. The registry gives a timeframe of up to 3 years. It does not report an observed primary outcome count, an analysis estimate, or uncertainty around that estimate. Without those results, the endpoint cannot be quantitatively interpreted.

What does a count show?

A count reports how many people met a specified outcome definition. Counts are most informative when readers can also identify the population at risk, the time period, outcome criteria, and completeness of observation. The safety record lists numbers at risk and numbers affected for serious and other adverse events in dose-specific groups. These are descriptive data. They do not, by themselves, explain why an event occurred or whether the event was caused by treatment.

In general, a proportion relates an event count to the number of people observed for that event. Its interpretation depends on the denominator and on whether participants had comparable opportunity for follow-up. The registry gives at-risk and affected counts within the safety groups, but it does not provide detailed follow-up duration or missingness information. It is therefore important not to read group counts as directly comparable risks without additional context.

Why would an interval matter?

In general, a confidence interval expresses the uncertainty around an estimate under the assumptions of the statistical method. It is not a guarantee that the true value lies within the interval, nor does it correct for bias or incomplete data. No confidence interval for the primary endpoint is reported in the registry record. The posted safety summary also does not provide intervals, so precision cannot be assessed from these counts alone. Small groups can yield imprecise estimates, but the actual uncertainty should be quantified rather than inferred from a point count.

What does the design allow?

The record describes a single-group study with dose-specific groups, and it does not report random allocation. The registry explicitly notes that the groups are not a like-for-like control comparison. General statistical reasoning requires caution when comparing nonrandomized groups: participant characteristics and clinical circumstances can differ, and those differences may influence outcomes. A difference in recorded event counts across dose groups is not, by itself, evidence of a causal dose effect.

The record does not state a statistical model for the primary endpoint, specify adjustment variables, or report hypothesis tests. It also lists zero analyses. A reader should not infer an analysis plan from the official title or from general conventions for early-phase trials. The analysis plan is not reported in the registry record.

How should planning illustrations be read?

Any sample-size figures associated with this analysis are planning illustrations, not the study's actual enrollment plan and not observed power. The described planning assumptions use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such assumptions describe a hypothetical comparison, whereas this study is recorded as single-group and does not have a randomized control arm. The registry record does not report the trial's own sample-size justification. Planning calculations should not be interpreted as evidence that the study was adequately powered or that a treatment effect was demonstrated.

General statistical methods can help clarify what additional information would be needed: a reported endpoint count, a clear analysis population, outcome definitions, follow-up details, and an appropriate estimate with uncertainty. Those elements are not available for the primary outcome in the posted record. The results should therefore be read as an incomplete statistical account, rather than as a basis for reconstructing an unreported analysis.

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("Fractionated Stereotactic Radiosurgery - 24 Gy", "Fractionated Stereotactic Radiosurgery - 27 Gy", "Fractionated Stereotactic Radiosurgery - 30 Gy", "Fractionated Stereotactic Radiosurgery - 33 Gy", "Fractionated Stereotactic Radiosurgery - 36 Gy")
n      <- c(4, 2, 3, 2, 9)
events <- c(0, 0, 0, 0, 0)
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  Fractionated Stereotactic Radiosurgery - 24 Gy  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  Fractionated Stereotactic Radiosurgery - 27 Gy  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8
ARM  Fractionated Stereotactic Radiosurgery - 30 Gy  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Fractionated Stereotactic Radiosurgery - 33 Gy  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8
ARM  Fractionated Stereotactic Radiosurgery - 36 Gy  9  0  0.0  0.0  33.6  -0.0  29.9  0.3  30.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures, including the primary DLT outcome and four named secondary outcomes: Best Response, Local Control of Disease, Regional Intracranial Failure, and Functional Assessment of Cancer Therapy - Brain (FACT-Br). The record lists zero analyses. It does not report a multiplicity strategy, such as prioritization among secondary outcomes or adjustment for multiple statistical tests. In general, testing several outcomes can increase the chance of a chance finding; a prespecified approach helps readers distinguish confirmatory analyses from exploratory ones. The registry record does not describe such an approach.

Missing-data handling is not reported in the registry record. The entry does not say how participants with incomplete follow-up, missing outcome assessments, or withdrawal were handled. It also does not provide the number included in each outcome analysis. The recorded enrollment is 20, but the number treated and the endpoint-specific analysis populations are not given. Enrollment should not be assumed to equal the number with complete outcome data.

The primary outcome population is described as all treated patients. The record does not state whether any different analysis population was used for safety or secondary outcomes, how the treated population was defined, or whether any sensitivity analyses were performed. There is no reported imputation method or account of outcome availability by dose group. These omissions limit assessment of whether the reported counts represent all eligible observations and whether incomplete follow-up could affect interpretation.

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: febrile neutropenia (25.0%).

The safety record presents serious adverse events, other adverse events, and deaths separately for each listed dose group. For 24 Gy, 1 of 4 at risk is recorded as affected by a serious adverse event, and 3 of 4 as affected by other adverse events; deaths are listed as 4. For 27 Gy, the corresponding counts are 0 of 3 for serious adverse events and 2 of 2 for other adverse events, with deaths listed as 1. For 30 Gy, the counts are 0 of 2 and 3 of 3, with deaths listed as 3. For 33 Gy, they are 0 of 3 and 2 of 2, with deaths listed as 2. For 36 Gy, they are 0 of 9 and 9 of 9, with deaths listed as 8.

These are registry counts, not causal findings. The record does not state that deaths were treatment-related, and the death counts should not be interpreted as such. It does not provide detail on event timing, recurrence, severity within the other-event category, or participant-level overlap among categories. Febrile neutropenia is listed among the top serious adverse event terms at 25.0%, but the record does not specify a dose group for that term. Differences between dose groups should be read cautiously because the design is not a randomized, like-for-like comparison and follow-up details are not reported.

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

The record establishes that a completed study examined fractionated stereotactic radiosurgery for large brain metastases, with dose groups listed from 24 Gy through 36 Gy. It describes the regimen as 24 to 36 Gy in 3 fractions (8-12 Gy/fx), identifies DLT as the primary outcome, and gives a timeframe of up to 3 years. It also reports safety counts by dose group and a serious adverse event term at 25.0%.

However, the key primary endpoint result is not reported in the registry record. There is no reported count of patients experiencing DLT, no estimate of uncertainty, and no analysis of the primary outcome. The record also does not give detailed results for the named secondary outcomes. As a result, the posted information cannot establish the observed frequency of DLT or characterize the secondary outcome findings.

The safety figures describe events recorded in the listed groups. They do not establish that radiation caused the events or deaths, and they do not support a reliable comparison of dose levels. The groups are not randomized controls, and the registry explicitly cautions that they are not a like-for-like control comparison. No comparison with another treatment or with no treatment is reported.

In general, a registry record can describe study plans and selected posted results, but incomplete outcome reporting limits what can be inferred. The status marked completed does not fill in unreported endpoint results, missing-data methods, or the statistical analysis plan. The record is therefore useful for understanding the study's stated question and the limited safety information posted, but it does not provide enough outcome evidence for a statistical conclusion about efficacy or comparative safety.

14. Why This Trial Matters Statistically

This study is statistically interesting because its primary outcome is a toxicity limit in a single-group radiation study, while the record also organizes safety counts by delivered dose. That structure raises distinct questions: how DLT was defined and counted, how dose groups were formed, and whether participants had comparable follow-up. The registry gives only a brief DLT definition and does not report the dose-assignment procedure or detailed assessment rules.

The study also illustrates why the design matters as much as the outcome counts. Dose-specific safety data can be useful descriptively, but the groups are not a randomized, like-for-like control comparison. Statistical comparisons across them would need careful consideration of how participants entered each group and what else differed between groups. The record does not provide those details, and it does not report a statistical analysis of dose differences.

Another important issue is outcome completeness. The primary endpoint is named and has a stated timeframe, yet its observed result is absent from the registry record. Secondary outcomes are listed, but their results and analyses are not reported. Without outcomes, analysis populations, and measures of uncertainty, readers cannot judge the precision of the findings or distinguish a stable pattern from an uncertain one.

These limitations are not unique to this record, but they are especially consequential when the aim is to characterize toxicity by dose. Clear outcome definitions, complete follow-up reporting, and transparent analysis methods help make early treatment research interpretable. The posted record offers some design and safety information, while leaving these core statistical questions unresolved.

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 registry record does not report the observed primary endpoint count, despite identifying DLT as the primary outcome. It also does not provide a confidence interval, a statistical test, or a dose-specific DLT result. The listed secondary outcomes do not have results or analyses in the posted record. This lack of outcome reporting prevents direct evaluation of the study's main statistical question.

Although the record gives a total enrollment of 20 and lists dose-specific safety counts, it does not give the number treated or clarify the number followed for each outcome. Follow-up completeness, censoring, withdrawal, and missing-data handling are not reported. The primary endpoint timeframe is up to 3 years, but the record does not show how much follow-up participants contributed or whether all had the opportunity for the full timeframe.

The dose groups are not a randomized control comparison. The registry does not explain dose assignment, eligibility by dose, or whether participant characteristics varied across groups. Therefore, group differences cannot be attributed to dose based on these counts. The record also does not report detailed adverse-event grading, timing, attribution, or the relationship of listed deaths to treatment.

Finally, the statistical plan, sample-size justification, multiplicity approach, and analysis populations are not reported in the registry record. The official title identifies the study as phase I, but the recorded phase is NA. These gaps limit both reproducibility and the strength of any inference drawn from the posted information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Fractionated Stereotactic Radiosurgery for Large Brain Metastases — NCT02054689.
• Registry record last updated 2025-05-28; status last verified 2025-05.
• Results first posted 2025-05-28.
• 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 NCT02054689, Fractionated Stereotactic Radiosurgery for Large Brain Metastases, as a completed single-group study with enrollment of 20. Its official title identifies it as a phase I study, while the recorded phase is NA. The study concerns fractionated stereotactic radiosurgery, described as 24 to 36 Gy in 3 fractions (8-12 Gy/fx), for people with large brain metastases and no prior whole brain radiation.

The primary outcome is the number of patients experiencing DLT up to 3 years, among all treated patients. Its observed result is not reported in the registry record. Dose-specific serious and other adverse-event counts and death counts are listed, but they do not establish causation or support randomized comparisons. The record lists secondary outcomes, but does not report their results or statistical analyses. Details of dose assignment, missing-data handling, and the statistical plan are also not reported.