Study of Intraoperative Radiotherapy for Patients With Large Brain Metastases Treated With Neurosurgical Resection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Intraoperative Radiotherapy for Patients With Large Brain Metastases Treated With Neurosurgical Resection (NCT04040400), a na na study. The primary outcome is Established Maximum Tolerated Dose.

2. Clinical Question

The study concerns IORT delivered after surgery for large brain metastases. Its stated purpose combines a dose-finding question with an interest in recurrence and progression-free survival. These are distinct aims: dose finding focuses on safety at successive dose levels, while recurrence and progression-free survival concern outcomes over follow-up. The registry record gives the dose-finding outcome as the primary outcome. Although the brief study description mentions progression-free survival and recurrence, no result or analysis for either is reported in the registry record.

The record lists an enrollment of 5 and a single treatment arm. It does not identify a control treatment or a usual-care comparison. Consequently, the record cannot support a comparative estimate of IORT versus another approach. The posted information is instead descriptive: it identifies the intended intervention and dose-escalation approach, and gives safety counts for the 18 Gy cohort. It does not report a numerical maximum tolerated dose or an analyzed estimate of recurrence or progression-free survival.

3. Trial Design

The study is titled as a Phase I/II study, but its phase field is listed as NA. It is an open-label study with masking listed as none, allocation listed as NA and a sequential model. These descriptions are consistent with dose escalation rather than a blinded randomized comparison. The University of Louisville is listed as sponsor. The record gives an enrollment of 5, a start date of 2019-10-23, a primary completion date of 2021-11-19 and a status of TERMINATED.

The planned treatment was intraoperative radiotherapy after neurosurgical resection of large brain metastases. The primary outcome description says that dose finding would use a classical 3+3 dose-escalation design. It describes starting at 18Gy, with a safety assessment for dose-limiting toxicities 90 days after treatment. Depending on that assessment, a subsequent cohort would receive either 18Gy or 21Gy. If escalation to 21Gy were permitted, a later assessment would guide whether a further cohort received 21Gy or 24 Gy. The record states that 24 Gy was the highest planned dose level if permitted by safety assessments.

The safety summary lists 5 participants at risk in the 18 Gy cohort and none at risk in either the 21 Gy or 24 Gy cohort. The difference between the planned cohort sequence described in the outcome text and the 5 participants listed for the 18 Gy safety summary is not explained in the registry record. The listed cohort counts do not establish whether the planned escalation decisions were made or why later cohorts have no participants recorded.

Termination status alone does not explain why the study ended. A reason for termination, actual dose-escalation decisions, and any departures from the planned sequence are not reported in the registry record. The record also does not describe a concurrent comparator arm, so the design does not provide a like-for-like treatment comparison.

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.

Cohort 1

Cohort 1:

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 Established Maximum Tolerated Dose, measured over Phase I cohorts; 90 days from treatments.

The primary outcome is titled Established Maximum Tolerated Dose. Its unit is participants, and its stated timeframe is Phase I cohorts; 90 days from treatments. The outcome description says that toxicity would be assessed using the National Cancer Institute Common terminology criteria for adverse events (version 5.0), with a safety assessment for dose-limiting toxicities after 90 days from treatment. The intended endpoint is therefore a dose-finding decision informed by toxicity observed after treatment, rather than a direct measure of tumor response.

In general, a maximum tolerated dose is used in dose-escalation research to identify the highest dose level judged acceptable under a protocol’s toxicity rules. It is a safety-oriented endpoint: the dose decision depends on both the observed toxicities and the prespecified decision process. The registry describes the dose levels and the timing of assessments, but it does not report the detailed toxicity threshold used to make the decision or a final dose determination.

The study description also mentions progression-free survival and recurrence of treated brain metastasis. Those are clinically relevant follow-up concepts, but they are not the posted primary outcome title. No progression-free survival result, recurrence result, follow-up summary or corresponding analysis is reported in the registry record. The available record therefore does not establish the status of that secondary aim.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical approach described in the registry is primarily a sequential safety and dose-finding design. The posted information does not include a completed analysis plan or outcome analysis. The explanations below distinguish the design concepts stated in the record from general statistical context.

How the dose-escalation design is described

The record says that dose finding would follow a classical 3+3 design. In general, this type of design evaluates a dose in a small cohort, waits for a specified safety observation period, and uses the observed dose-limiting toxicities to decide whether to remain at that dose or move to another dose level. It is a rule-based sequence: the decision at one dose guides which dose is given next. It is not a randomized comparison of treatment against a control group.

For this study, the registry describes an initial dose of 18Gy and a 90-day safety assessment. It states that the assessment would guide whether the next cohort received 18Gy or escalated to 21Gy. If escalation to 21Gy were permitted, another assessment would guide whether the next cohort received 21Gy or escalated to 24 Gy. The stated maximum planned dose was 24 Gy, conditional on the safety assessments. The registry does not give the detailed decision thresholds or report the resulting decisions. A description of a planned algorithm is not evidence that every step was completed.

What an endpoint of maximum tolerated dose means

In general, dose-finding trials use toxicity observations to select a dose for further evaluation. The selected dose is conditional on the protocol’s toxicity definitions, assessment window and decision rules. It is not a universal biological boundary, nor does the phrase alone indicate the probability of a particular adverse event for an individual. Here, the record identifies toxicity criteria by reference to the National Cancer Institute Common terminology criteria for adverse events (version 5.0) and identifies a 90-day assessment window. The precise dose-limiting-toxicity definition and final dose decision are not reported in the registry record.

The endpoint title identifies a dose determination, and the unit is participants. However, no analysis result is posted. The safety counts cannot be substituted for the missing dose-finding decision because the record does not report the complete decision rules or how the observed counts were applied to them.

How to interpret the safety counts

Counts describe how many participants are listed in the safety categories; they are not, by themselves, estimates adjusted for follow-up or other characteristics. The registry reports 5 at risk and 5 affected for serious adverse events in the 18 Gy cohort, along with 5 at risk and 1 affected for other adverse events, and 4 deaths. The record does not explain whether the categories overlap or give the attribution and timing needed to interpret causal relationships. The listed serious adverse event terms are descriptive labels, not comparative tests.

In general, uncertainty around event estimates matters especially when the number of participants is small. A confidence interval describes a range of values compatible with the data under a specified statistical model and assumptions; it does not guarantee that the true value lies within that range. No confidence intervals for the adverse event counts are reported in the registry record. There is no basis in the record to attach a more precise inferential interpretation to these counts.

Comparative tests and planning calculations

No control arm or randomized allocation is listed. Statistical tests designed to compare two treatment groups would not create a valid randomized comparison in this sequential, single-arm record. Any comparisons among dose levels would also be limited because only the 18 Gy cohort has participants recorded in the safety summary. The record does not report comparative analyses.

General planning calculations can illustrate how many participants per arm might be needed to detect an assumed effect under specified statistical assumptions. They are not observed results and do not indicate the probability that this study detected an effect. The stated planning assumptions use a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect expressed as a fraction of an observed effect. Those assumptions are described as planning illustrations, not as the trial’s design. They do not turn this study into a two-arm comparison or replace a trial-specific sample-size justification. The registry record does not report such a justification, and no computed planning results are included in the record.

In general, over-dispersion means that outcome variability is greater than a statistical model expects. It can make standard errors too small and confidence intervals too narrow if the model does not account for the extra variability. That concept is relevant when choosing models for outcomes with variability beyond the assumed distribution. The registry record does not report a model-based analysis of the study outcomes or an assessment of over-dispersion.

More broadly, inference depends on the outcome definition, analysis population, follow-up, missingness and statistical model. The record supplies limited descriptive safety information but no primary-outcome analysis. As a result, there are no reported model estimates, p-values or confidence intervals to assess. The design description clarifies what was intended; it does not supply the missing results.

10. Multiplicity, Missing Data and Analysis Populations

The registry describes more than one study aim: establishing a maximum tolerated dose and determining progression-free survival in terms of recurrence of treated brain metastasis. The posted primary outcome is the maximum tolerated dose. No analysis of either aim is reported. The record does not state whether the outcomes were arranged in a formal hierarchy, whether one was designated secondary, or how multiple outcomes or tests would be handled. A multiplicity adjustment or testing sequence is not reported in the registry record.

In general, multiplicity arises when several hypotheses or outcomes are tested. Without an appropriate plan, interpreting multiple p-values as if they were a single prespecified test can overstate the strength of evidence. This general concern does not establish that a particular adjustment was necessary or omitted in this study; the statistical plan is not reported in the registry record.

Missing-data methods, reasons for missing observations, follow-up completeness and censoring rules are also not reported. The registry lists an enrollment of 5 and four deaths in the 18 Gy safety summary, but it does not explain the timing or outcome implications of those deaths. No analysis population is identified, and there is no description of whether all enrolled participants were included in each outcome analysis. Since no outcome analyses are posted, it is not possible to assess how missing outcome information was handled.

In general, missingness can affect an estimate when the availability of an outcome is related to participants’ health, treatment or follow-up. The appropriate approach depends on the outcome and the reasons observations are absent. No such assessment can be reconstructed from the registry record. The absence of reported methods should not be interpreted as evidence that missing data were absent or that a particular method was used.

11. 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: respiratory failure (20.0%), acute kidney injufy (20.0%), worsening malignancy (20.0%), thromboembolic event (20.0%), meningitis - bacterial (20.0%).

For the 18 Gy cohort, the registry lists 5 participants at risk and 5 affected in the serious adverse event category. For other adverse events, it lists 5 at risk and 1 affected. The same cohort summary lists 4 deaths. These figures are registry counts; the record does not provide a causal assessment, event timing or an explanation of whether people appear in more than one category.

The serious adverse event list includes Respiratory Failure, Acute Kidney Injufy, Worsening Malignancy, Thromboembolic Event, Meningitis - Bacterial and Altered Mental Status, each reported at 20.0%. The listed percentages do not give details about severity grades, duration, attribution or overlap among terms. The record does not explain the spelling of Acute Kidney Injufy, so it is retained as recorded.

No participants are listed in the 21 Gy and 24 Gy safety cohorts. This is not a finding of zero risk at those doses; the record contains no cohort participants from whom to characterize adverse events at those levels. Because there is no concurrent comparator, these counts do not establish a difference from another treatment. The registry record does not report whether events were considered related to IORT.

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

The record documents a study intended to evaluate IORT after resection of large brain metastases through sequential dose escalation. It gives planned doses and a 90-day safety-assessment process. The safety summary contains counts for the 18 Gy cohort, including serious adverse events, other adverse events and deaths. Those details describe what is recorded; they do not amount to a complete analysis of treatment safety or effectiveness.

The registry does not report the primary endpoint result. It therefore does not identify an established maximum tolerated dose. The fact that higher dose cohorts have no participants recorded means the available safety summary cannot describe experience at 21Gy or 24 Gy. The record also does not report the progression-free survival or recurrence results mentioned in the study purpose. It does not show an analyzed treatment effect against a control group.

In general, a safety count is not the same as evidence that a treatment caused an event. Causal interpretation requires information about timing, attribution, alternative explanations and the study design. Those details are not reported in the registry record. Likewise, the listed deaths are a safety summary item, not a standalone estimate of treatment-related mortality.

The small enrollment and absence of outcome analyses limit the precision and scope of interpretation. No confidence intervals or model results are posted for the primary outcome. Without such analyses, readers cannot assess the uncertainty around an endpoint estimate or evaluate a statistical comparison. The registry’s terminated status does not explain the reason for termination or establish whether all planned follow-up occurred.

The most defensible interpretation is therefore narrow: the registry records a sequential dose-finding study with 5 enrolled participants, safety information for the 18 Gy cohort, and no reported primary outcome analysis. The record does not establish a selected dose, quantify progression-free survival or recurrence, or support a comparative conclusion.

13. Why This Trial Matters Statistically

This study is statistically important as an example of the distinction between a protocol’s intended question and the results available for interpretation. A dose-escalation design is organized around sequential safety decisions. Each decision depends on toxicity observations at the current dose and on prespecified rules. The registry describes that intended process, but does not report the dose decisions or a final maximum tolerated dose. Without the endpoint result, the central dose-finding question remains unanswered in the posted record.

The record also illustrates why descriptive safety counts need context. A count of affected participants is informative about what the registry lists, but it does not establish causation, comparative safety or precision. Timing, attribution, definitions and follow-up all shape interpretation. The summary provides limited information on those features, and no uncertainty intervals or model-based estimates are reported.

Design and enrollment matter for the scope of inference. This is a sequential study with no randomized comparator listed. It cannot be read as a controlled estimate of the effect of IORT relative to another treatment. The absence of participants recorded at the higher dose levels also means the safety summary does not characterize those doses. Neither a planned escalation nor a dose level named in the protocol is equivalent to an observed cohort result.

Finally, a terminated record with no posted primary analysis highlights the difference between reporting study conduct and reporting inferential results. Enrollment, dates, status and adverse event counts offer useful context, but they do not answer the trial’s primary statistical question. Clear reporting of outcome definitions, analysis populations, missing data, decision rules and final dose conclusions would be necessary for a fuller statistical interpretation; those details are not reported in the registry record.

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 registry record does not report the reason for termination, actual dose-escalation decisions or a final maximum tolerated dose. Although it describes a planned 3+3 sequence, the safety summary lists 5 participants in the 18 Gy cohort, and the record does not explain this difference. It lists no participants in the 21 Gy or 24 Gy cohorts, so there is no safety experience reported for those levels.

The primary endpoint has no posted analysis, and no progression-free survival or recurrence analysis is reported despite those aims appearing in the study description. The record does not provide a detailed dose-limiting-toxicity definition, dose-decision thresholds, a complete statistical analysis plan, analysis populations, or methods for missing data and follow-up. It also does not report event attribution, timing, overlap between adverse event categories, or causes of death.

With no comparator arm, the record cannot supply a randomized comparative estimate. The limited enrollment and lack of inferential results further restrict what can be said about precision. No confidence intervals accompany the posted safety counts. The record does not provide enough information to determine whether all planned assessments were completed or how the available observations relate to the planned endpoints. These limitations do not establish what the unreported results would have been; they define what cannot be concluded from the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of Intraoperative Radiotherapy for Patients With Large Brain Metastases Treated With Neurosurgical Resection — NCT04040400.
• Registry record last updated 2023-10-12; status last verified 2023-10.
• Results first posted 2023-10-12.
• 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

NCT04040400 is a University of Louisville study of intraoperative radiotherapy following neurosurgical resection for large brain metastases. The record describes a sequential, open-label dose-escalation design and lists no randomized allocation or masking. Enrollment is 5, and the study status is TERMINATED.

The planned dose-finding approach describes safety assessments 90 days after treatment and dose levels of 18Gy, 21Gy and 24 Gy, with escalation conditional on safety. The posted primary outcome is establishment of the maximum tolerated dose, but the registry reports zero analyses and no primary outcome result. It also does not report results for the stated progression-free survival and recurrence aims.

The safety summary lists 5 participants at risk in the 18 Gy cohort, 5 affected in the serious adverse event category, 1 affected in the other adverse event category and 4 deaths. The higher-dose cohorts have no participants recorded. The registry does not explain the termination, report a final dose determination, or provide a comparative treatment analysis.