A Randomized Comparison of Radiation Therapy Techniques in the Management of Node Positive Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Randomized Comparison of Radiation Therapy Techniques in the Management of Node Positive Breast Cancer (NCT00581256), a randomized phase 1, phase 2 study. The primary outcome is The Number of Participants With a Significant Increase in Perfusion Defects (PD).

2. Clinical Question

The clinical rationale in the registry summary is that radiotherapy can reduce breast-cancer-specific mortality in patients at high risk for distant dissemination, while heart and lung exposure may contribute to cardiovascular and pulmonary toxicity. The study therefore focused on comparing radiation-planning techniques using indicators of potential cardiac and lung toxicity, rather than reporting long-term clinical cardiac or pulmonary toxicity as its primary focus.

The stated research aim was to assess whether IMRT results in less radiation exposure to the heart and lungs than the best current 3-dimensional technique. The primary endpoint described in the record is a perfusion-defect measure, not a direct measure of long-term clinical events. The available record does not report a single arm-to-arm primary endpoint result, so it does not establish whether either technique produced fewer significant perfusion-defect increases.

3. Trial Design

This was a randomized, parallel-group study with no masking. The registry lists Phase 1 and Phase 2, while its study summary describes the comparison as a Phase II randomized trial. The study was marked completed. Enrollment was 54. The sponsor was the University of Michigan Rogel Cancer Center.

The two interventions were radiation techniques: IMRT and 3D radiotherapy. The arm descriptions specify best delivery-optimized radiotherapy for IMRT and the best 3-dimensional standard PWTF technique for the comparator. The registry gives a start date of 2006-04 and a primary completion date of 2015-04.

Randomization means treatment assignment was intended to be determined by chance, which can help reduce systematic differences between groups at the start of a study. The record does not report the randomization sequence-generation method, allocation concealment, or whether allocation was balanced in practice. It also does not report masking; the study is explicitly listed as having none.

The registry describes the trial as generating preliminary data to inform a possible later multi-institutional comparison using long-term clinical cardiac and pulmonary toxicity as endpoints. That proposed future study is not the same as the endpoint described for this trial. The record does not provide a protocol rationale for the enrollment target, details of recruitment, or a statistical analysis plan.

There are four outcome measures and two analyses listed in the record, but the primary outcome has several categories or time points and is not reduced to one comparison in the available summary. Accordingly, the design information establishes the randomized treatment comparison and intended focus, but does not by itself provide an estimate of the primary endpoint effect.

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

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 The Number of Participants With a Significant Increase in Perfusion Defects (PD), measured over 1 Year.

The primary endpoint is described as the number of participants with a significant increase in perfusion defects after breast-cancer radiotherapy. The timeframe is 1 Year. Perfusion distributions were assessed relative to the institution’s normal polar-map databases for the left anterior descending artery. The description defines significance using two SD thresholds: an increase greater than 5% for the 2.5-SD threshold, or greater than 10% for the 1.5-SD threshold.

In general, a participant-count endpoint records how many people meet a prespecified event definition. It can be useful when the clinical question concerns whether a defined change or event occurs, rather than the average size of a measurement across all participants. Here, the event is a qualifying increase in a perfusion-defect measure. The threshold is important: it distinguishes changes considered significant under the endpoint definition from changes that do not cross that definition.

The endpoint is an indicator of potential cardiac toxicity, not a direct record of a clinical cardiac event. The registry also lists a secondary outcome for mean percent change in ejection fraction, as well as outcomes concerning new lung perfusion defects, pericarditis, and pneumonitis. Those measures address different aspects of potential toxicity and should not be treated as interchangeable with the primary perfusion-defect count.

The record does not report one consolidated primary endpoint comparison or its uncertainty. The number of participants meeting each threshold by arm is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does randomization contribute?

In general, random assignment is used to make treatment groups comparable in expectation with respect to both measured and unmeasured characteristics. It can support a causal comparison when the assigned groups are analyzed appropriately and outcome ascertainment is sufficiently complete. Randomization does not guarantee that groups will be identical, especially in a study with limited enrollment, and it does not remove the need to report the outcome data and analysis method. The registry identifies this study as randomized, but the sequence-generation and allocation-concealment methods are not reported in the registry record.

What kind of outcome is described?

The primary endpoint is a count of participants meeting a defined event threshold. A binary outcome gives each participant an event status: the event definition is either met or not met. Group-level event counts can be translated into event proportions when denominators are known, and a treatment comparison can then be expressed using an appropriate effect measure. Those are general approaches, not a description of an analysis confirmed for this trial. The registry record does not report a single primary comparison or its analysis method.

The perfusion-defect endpoint depends on both the underlying measurement and the chosen threshold. The record describes normalized perfusion distributions relative to normal polar-map databases and specifies two SD thresholds. It treats increases greater than 5% or 10% as significant under the 2.5-SD and 1.5-SD thresholds, respectively. When an endpoint has multiple thresholds or categories, each definition can identify a different set of participants. A report should make clear which definition is being used for each comparison, and whether the definitions are separate outcomes or components of a combined outcome. The available summary does not provide one reduced comparison.

How should uncertainty be understood?

In general, an effect estimate is a numerical description of the difference or relationship observed in the study. A confidence interval communicates the statistical uncertainty around that estimate under the chosen model. For a binary outcome, uncertainty depends on the event information and the group sizes; sparse events can yield imprecise estimates. A p-value is another summary tied to a specified statistical test and null hypothesis. It should not be used alone to judge how large or important a difference is. The primary endpoint estimates, confidence intervals, and p-values are not reported in the registry record.

Does the record identify the statistical model?

No primary endpoint model or test is reported in the registry record. The record does not state whether the analysis was adjusted, which covariates might have been used, how the two thresholds were handled, or how repeated measurements or multiple time points were handled. General statistical practice would require the analysis to match the endpoint structure and the prespecified question; the particular choices for this trial cannot be inferred from the outcome description alone.

What does the planning illustration mean?

The record describes sample-size planning illustrations based on a stated fraction of the observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation. It also distinguishes participant-per-arm illustrations from total-event illustrations for time-to-event outcomes. These assumptions describe planning calculations, not the trial’s original design rationale and not observed power. A planning illustration is conditional on its assumptions and effect target; it does not show that the completed trial had a particular probability of detecting an effect. The numeric planning results and the effect used for the primary endpoint are not reported in the available record, so no numerical planning interpretation can be made.

Why does event rarity matter?

As a general statistical point, when events are uncommon, a small change in the number of observed events can materially affect an estimated event proportion or relative comparison. Methods that rely on large-sample approximations may also be less reliable with sparse data. Analysts may consider methods suited to sparse outcomes, but the choice depends on the endpoint, the analysis plan, and the available data. The registry record does not specify a method for handling sparse events for the primary endpoint.

What can be inferred from the listed adverse-event counts?

Counts describe observed events in the listed groups; by themselves they do not give a complete comparative safety analysis. A comparative analysis would need a defined event window, clear denominators, handling of participants with multiple events, and an appropriate method for uncertainty. In general, participant counts and event counts can differ if one participant experiences more than one event. The adverse-event information in the record gives participants at risk and affected for the reported categories, but does not describe a complete inferential safety analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists four outcome measures and two analyses. The primary endpoint description includes two SD thresholds and says that several categories or time points were not reduced to one comparison. When a study evaluates multiple outcomes, thresholds, time points, or analyses, there can be more than one opportunity to observe a result that appears noteworthy by chance. In general, a prespecified testing hierarchy or an adjustment for multiple comparisons can help define how such results should be interpreted.

The multiplicity strategy is not reported in the registry record. The record does not say which endpoint comparison was designated for confirmatory testing, whether the two thresholds were analyzed separately, or whether any adjustment was applied. It is therefore not possible to determine how any potential multiplicity was handled.

Missing-data methods and analysis populations are also not reported in the registry record. The registry entries do not describe how participants without a follow-up perfusion assessment were handled, whether all randomized participants were included in the primary analysis, or whether the analysis followed assigned treatment. Those choices can affect interpretation, particularly if missing outcome measurements differ between groups or are related to participants’ health or treatment experience.

In general, an intention-to-treat analysis compares participants according to their randomized group, while other analysis populations may apply additional eligibility or treatment-completion rules. The record does not identify which population was used. No assumptions should be made about missing outcomes, exclusions, or interim analyses; these details are not reported in the registry record.

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: infection with normal anc or grade 1 or 2 neutrophils (3.6%).

The serious adverse-event figures list 1 participant affected among 28 at risk in the IMRT group and 0 among 26 at risk in the 3DRT group. The record also lists other adverse events: 27 participants affected among 28 at risk in the IMRT group and 23 among 26 at risk in the 3DRT group. These are descriptive counts, not estimates of a causal treatment effect.

The registry lists “Infection with normal ANC or Grade 1 or 2 neutrophils” as a top serious-event term, with 3.6%. The available record does not provide enough context to interpret that percentage as a between-group comparison or to determine its relationship to the group-level serious-event counts.

Adverse-event counts should be read with attention to the event definitions and reporting period. The record does not give the safety follow-up window, details about event severity beyond the serious-event grouping, or an inferential comparison. The listed counts do not establish that one technique has a safer overall profile, and they do not answer the primary perfusion-defect question.

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

The record’s main statistical contribution is its description of a randomized comparison of two radiotherapy techniques and a quantitative endpoint intended to assess myocardial perfusion changes. It also records several other outcomes related to cardiac and lung toxicity. The clinical motivation is to investigate whether a planning and delivery approach could reduce heart and lung exposure compared with a standard 3-dimensional approach.

However, the available record does not provide a single primary endpoint comparison, group-level primary outcome counts, or a measure of uncertainty. It therefore does not support a conclusion about the direction, size, or precision of the primary treatment difference. The adverse-event figures offer descriptive information but are not a substitute for a complete comparative analysis.

A significant perfusion-defect increase is a defined measurement outcome. It should not be interpreted as equivalent to a clinical cardiac event or to long-term cardiac disease. The registry summary explicitly presents these measures as indicators of potential toxicity and describes long-term clinical cardiac and pulmonary toxicity as endpoints for a possible future study.

In general, an endpoint can be relevant to a clinical hypothesis without answering every clinically important question. A measured change may provide evidence about a physiological indicator, while questions about symptoms, long-term morbidity, or mortality require appropriate outcomes and follow-up. The record does not report long-term clinical toxicity results for this comparison.

Accordingly, the record documents the study question, design, endpoint definitions, and some adverse-event counts, but leaves key information needed to interpret the primary treatment effect unreported. Neither superiority, equivalence, nor absence of effect can be concluded from the information available.

13. Why This Trial Matters Statistically

This trial is statistically interesting because it links a technical question about radiation delivery to measurable indicators of potential cardiac and pulmonary toxicity. The comparison is randomized, and the endpoint definition uses quantitative perfusion information and specified thresholds. Such an endpoint can make a treatment-planning question measurable, while still requiring careful interpretation of what the measurement represents.

The study also illustrates the distinction between a surrogate or physiological indicator and a later clinical outcome. The registry summary describes perfusion defects and other toxicity indicators as preliminary measures and identifies long-term clinical cardiac and pulmonary toxicity as possible endpoints for a future multi-institutional comparison. Results on an indicator would not, on their own, establish the effect on those longer-term outcomes.

From a statistical perspective, the endpoint’s multiple thresholds and the record’s reference to several categories or time points make transparent reporting especially important. A clear primary contrast, analysis population, missing-data approach, and uncertainty estimate are necessary to judge how strongly the observed data address the trial question. Those details are not reported in the available registry record.

The record also shows why descriptive safety counts need context. Counts are useful for documenting what was recorded, but interpretation requires consistent event definitions, follow-up information, denominators, and a suitable comparative analysis. The available safety figures should not be read as a full account of comparative safety.

Overall, the trial matters as a randomized evaluation of a radiotherapy-planning question, while the reporting limits what can be concluded from its primary endpoint. The distinction between a carefully framed research question and a fully interpretable result is central to evaluating clinical evidence.

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 most important trial-specific limitation in the available record is that the primary endpoint is not reduced to one comparison. The endpoint description refers to multiple thresholds, and the record notes several categories or time points. Group-level primary outcome counts, an effect estimate, and its uncertainty are not reported in the registry record.

The record does not report the statistical analysis plan, the primary analysis population, missing-data handling, or the approach to multiple thresholds and outcomes. It also does not describe the randomization sequence or allocation concealment. These omissions prevent assessment of how the planned comparison was implemented and how robust any result would be to analytic choices.

The endpoint is a perfusion-defect measure intended as an indicator of potential cardiac toxicity. It is not itself a long-term clinical cardiac outcome. The registry summary describes longer-term clinical cardiac and pulmonary toxicity as endpoints for a possible later study, and those results are not reported in the available record.

Safety information is limited to the listed adverse-event counts and a serious-event term. The safety follow-up period, detailed event definitions, and comparative statistical analysis are not reported in the registry record. The registry entries available also do not give fuller participant characteristics or explain how enrollment was determined.

These are limitations of what can be established from the registry record; they should not be taken as evidence that the unreported methods or analyses were absent from the conduct of the study.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Randomized Comparison of Radiation Therapy Techniques in the Management of Node Positive Breast Cancer — NCT00581256.
• Registry record last updated 2017-10-31; status last verified 2017-09.
• Results first posted 2016-12-01.
• 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

NCT00581256 is a completed randomized, parallel-group study with no masking, sponsored by the University of Michigan Rogel Cancer Center. The registry lists Phase 1 and Phase 2, enrollment of 54, a start date of 2006-04, and a primary completion date of 2015-04.

The study compared IMRT with a standard 3-dimensional PWTF radiotherapy technique in node-positive breast cancer. Its primary endpoint concerns the number of participants with a significant increase in perfusion defects at 1 Year, using specified thresholds. The record lists four outcome measures and two analyses, but does not provide a single primary endpoint comparison or its statistical result.

Adverse-event counts are listed for both groups, but the available record does not report a complete comparative safety analysis. The primary endpoint analysis method, missing-data handling, analysis population, and multiplicity approach are not reported in the registry record.