Breast VCEUS to Evaluate Early Response to Neoadjuvant Chemotherapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Breast VCEUS to Evaluate Early Response to Neoadjuvant Chemotherapy (NCT01817374), a na na study. The primary outcome is Tumor Volume Measure Using Grayscale US.

2. Clinical Question

The imaging schedule described in the record includes a baseline visit before treatment and an early-treatment visit at 14 (± 4 days) after initiation of chemotherapy. A further assessment is listed at 28 days (± 4 days) after initiation. These are planned imaging timepoints; the record does not report how many participants completed each assessment or whether all planned measurements were obtained.

The study also stated an aim to assess the incremental benefit of quantitative VCEUS relative to planar contrast-enhanced ultrasound tumor perfusion measurements and enhancement patterns. The registry record does not report results for that aim. It lists Pathology Residual Tumor as a secondary outcome, but does not provide its result. As a result, the record sets out a clinical imaging question without posting the estimates needed to evaluate how well the imaging measures tracked treatment response.

3. Trial Design

NCT01817374 is a pilot study titled “Breast VCEUS to Evaluate Early Response to Neoadjuvant Chemotherapy.” The registry lists the study as terminated, with enrollment of 6. The recorded start is 2015-06 and primary completion is 2016-07. The phase is listed as NA. The sponsor is the University of Alabama at Birmingham.

The design is listed as single-group, with allocation NA and masking NONE. Participants with breast cancer receiving neoadjuvant chemotherapy were to undergo 2D grayscale imaging followed by quantitative VCEUS. The described schedule includes imaging at baseline, at 14 (± 4 days) after treatment initiation, and at 28 days (± 4 days) after treatment initiation. The registry description available for the imaging schedule ends after this information, so further visit details are not reported in the registry record.

There is no separately assigned control arm described. Grayscale ultrasound is part of the imaging procedure and is also named as the primary outcome measure; that does not make it a randomized comparator. The study summary describes comparisons with co-temporal grayscale ultrasound, mammography findings, planar CEUS measurements, pathology, and clinical outcome as objectives. Comparative estimates and results are not reported in the registry record.

The registry lists nine outcome measures and zero analyses. No statistical analysis plan, sample-size justification, interim analysis plan, or specific handling of the pilot design is reported in the registry record. A planning illustration based on an observed effect is not evidence that the study was designed or powered to test a particular effect. Its stated assumptions involve equal allocation between two arms, whereas this study is listed as single-group; that planning framework should therefore not be read as the trial’s own design or as observed power.

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: Recruitment for this study started in June 2015. The primary completion point was reached at July 2016, and study completion July 2016. The study was conducted at the University of Alabama at Birmingham.

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.

Population: Total number of participants is 6. All participants received both interventions.

6. Primary Endpoint

The registry lists the primary outcome as Tumor Volume Measure Using Grayscale US, measured over Baseline (first visit).

The primary outcome is titled “Tumor Volume Measure Using Grayscale US.” It is a continuous measure described as the mean grayscale ultrasound size, in millimeters, along the longest axis at baseline (first visit). The description gives a minimum of 21.0 millimeters and a maximum of 82 millimeters for the grayscale measurement range. These range limits describe the measure; they are not a reported treatment effect or a group-level result.

In general, a longest-axis measurement offers a direct dimensional summary of a visible tumor. Repeating a size measurement during treatment can be useful for describing changes in tumor dimensions, while grayscale ultrasound provides the standard-of-care imaging reference identified in this study description. A baseline measure can characterize tumor size before the planned early-treatment assessments, but by itself it does not show how a tumor changes over time or whether imaging predicts pathology.

The record identifies the summary statistic as a mean with standard deviation. It does not report the baseline mean, standard deviation, participant-level measurements, or an estimate comparing measurements across visits. It also does not report a definition of response based on this endpoint. Consequently, the endpoint’s measurement scale and timing are clear, but the observed distribution and any relationship to clinical response cannot be evaluated from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is continuous: grayscale ultrasound size along the longest axis, measured in millimeters. The registry specifies a mean and standard deviation as its summary format. In general, the mean describes the central value of a set of measurements, while the standard deviation describes how dispersed those measurements are around the mean. The registry record does not report either summary statistic for this endpoint, so the observed baseline size distribution cannot be described from the posted information.

What would repeated imaging contribute?

In general, repeated measurement can show whether a measured feature changes during follow-up. For this study, the described imaging schedule includes baseline, 14 (± 4 days) after treatment initiation, and 28 days (± 4 days) after treatment initiation. A longitudinal analysis could account for the fact that multiple measurements from the same participant are related rather than independent. The registry record does not identify a longitudinal model, report visit-specific measurements, or state how measurements outside the planned timing windows would be handled.

The study description proposes assessing early response and comparing VCEUS with grayscale ultrasound, mammography, and pathology or clinical outcomes. In general, a prediction analysis needs a clearly defined target outcome and a reported measure of predictive performance, together with uncertainty and a description of the model or rule used. Those analysis details and estimates are not reported in the registry record. The stated aims should not be mistaken for completed analyses.

Why does variability matter?

In general, standard deviation describes variation among measurements, while a standard error describes uncertainty in an estimated summary. They answer different questions. If repeated measurements show variability beyond what a simple model assumes, an analysis may need to account for that extra variation; this is often called over-dispersion. Accounting for it can prevent uncertainty from being understated. The registry record does not report a variability estimate, an over-dispersion assessment, or a model for this study, so no such adjustment can be attributed to the posted analysis.

A confidence interval is generally used to communicate estimation uncertainty, and a p-value is generally used to assess compatibility between data and a specified null model. Neither provides a substitute for the estimate itself or for understanding the analysis assumptions. The registry record reports no confidence interval, p-value, hypothesis test, or model-based result for the primary endpoint or the response objectives. There is consequently no basis in the record to characterize evidence strength or precision for those objectives.

How should planning calculations be read?

In general, a sample-size calculation uses an assumed effect, variability, allocation, significance level, and power target to illustrate the amount of information a future study might require. Such calculations are planning illustrations, not observed power and not results from the enrolled participants. The stated planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a fraction of an observed effect. They specify participants per arm for non-time-to-event outcomes.

Those assumptions describe a two-arm planning framework, while the registry lists this study as single-group. The registry record does not report a trial-specific sample-size justification or an observed effect estimate on which to ground a planning illustration. The assumptions therefore should not be interpreted as the study’s protocol, as a justification for enrollment, or as evidence about the study’s power. Any planning values should be understood as hypothetical illustrations rather than observed findings.

The registry lists zero analyses. It does not identify the software, estimator, model, covariate adjustment, missing-data method, confidence-interval method, or decision rule used for an analysis. Because no recalculated outcome statistics are reported, there is no recalculated result to compare with a sponsor analysis. General statistical explanations describe possible approaches, not methods confirmed for this study.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Grayscale Ultrasound")
n   <- c(6)
m   <- c(38.2)
sp  <- c(23.9)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Grayscale Ultrasound  6  38.200  23.900  13.118  63.282

11. Multiplicity, Missing Data and Analysis Populations

The registry lists nine outcome measures and zero analyses. It names Tumor Volume Measure Using Grayscale US as the primary outcome and Pathology Residual Tumor as a secondary outcome. The record also describes several study aims involving imaging comparisons and response assessment. It does not report a multiplicity strategy, such as whether or how inference across multiple outcomes or comparisons would be adjusted.

In general, multiplicity arises when several outcomes or hypotheses are examined: interpreting each result as if it were the only analysis can make chance findings more likely across the set. A prespecified analysis plan helps clarify which outcomes are primary and how any additional comparisons will be interpreted. Here, the registry designation of a primary outcome is available, but the analysis plan and multiplicity handling are not reported in the registry record. No claim of adjustment or control of false-positive findings can be made.

The analysis population is not described in the endpoint information. The record does not report whether analyses were intended to include all enrolled participants, only those with complete imaging, or another population. It also does not report the number with evaluable measurements at each visit, withdrawals, or reasons for missing data. The methods for handling missing measurements, incomplete follow-up, or measurements taken outside the specified timing windows are not reported in the registry record.

In general, missingness can affect an estimate when the availability of a measurement is related to the measurement itself or to participant characteristics. The appropriate interpretation depends on the pattern of missingness, the analysis population, and the method used. None of those details can be established from the posted record. The enrollment count should not be assumed to equal the number contributing to every endpoint or visit.

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.

The safety record lists a Definity VCEUS group. For serious adverse events, 6 participants are recorded as at risk and 0 as affected. For other adverse events, 6 are recorded as at risk and 0 as affected. Deaths are recorded as 0, and no top serious-event terms are listed.

These entries are counts in the registry record, not proof that the procedure has no risk. A zero affected count means that no affected participants are recorded in these fields; it does not establish that every possible event was assessed, that all follow-up was complete, or that an event could not occur. The record does not provide event-level descriptions, severity breakdowns beyond the serious/other categories, timing, relatedness assessments, or a narrative of safety monitoring.

The study summary says Definity® is FDA approved for use as an ultrasound contrast agent for echocardiography and that breast use in this study would be off-label. It also states that administration would follow total-dose guidelines approved by the FDA. The safety counts should be read in that study context and within the limits of what the registry record reports; they are not a comprehensive safety profile.

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

The record establishes that a pilot study of quantitative VCEUS for early breast cancer response assessment was registered as a single-group study, enrolled 6, and is now listed as terminated. It describes a planned imaging workflow using grayscale ultrasound and quantitative VCEUS during neoadjuvant chemotherapy. It also identifies a baseline grayscale ultrasound tumor-size measure and posts safety counts for the Definity VCEUS group.

It does not establish whether VCEUS accurately identified response, whether it added predictive information beyond grayscale ultrasound or other imaging, or whether imaging findings corresponded with surgical pathology or clinical outcome. Those are stated aims, but outcome estimates and analyses are not reported in the registry record. The baseline endpoint description alone cannot answer questions about change over treatment or prediction.

In general, a small exploratory study may be useful for learning about procedures and generating questions for future research, but that general possibility is not evidence that this study achieved a particular feasibility goal. The registry does not report feasibility criteria, completion by visit, or reasons for termination. It also does not report analysis populations, missing-data handling, confidence intervals, or a statistical analysis plan. The record therefore does not permit a quantitative judgment about precision or reliability.

The absence of a randomized comparison also limits causal interpretation. The design does not compare assigned treatment groups, and the record provides no direct basis for attributing any observed clinical change to an imaging method. More fundamentally, no such change or relationship is posted. The study description should be read as documenting an intended evaluation, not as a claim that an imaging approach succeeded or failed.

The safety entries report zero affected participants in the recorded serious and other adverse-event categories, with 6 at risk in each. These counts are limited to the information recorded and do not rule out unrecorded events or establish general safety. Overall, the registry supports a careful account of the study’s design and stated objectives, while leaving the central efficacy and predictive questions unanswered.

14. Why This Trial Matters Statistically

This study is statistically instructive because its research question concerns prediction, while the available primary outcome is a baseline measurement of tumor size. Those are related but different statistical tasks. Describing a baseline tumor dimension is not equivalent to testing whether an imaging measure detects early response or predicts residual tumor at surgery. Clear separation between measurement description, longitudinal change, and prediction is essential when reading a study record.

The single-group design also highlights the distinction between a within-participant comparison and a controlled comparison. Repeated imaging can potentially describe change over time, but that alone does not determine whether one imaging method adds information beyond another or whether a treatment caused a change. A study intended to support those conclusions needs results and analysis methods matched to the question. The registry record states comparison objectives but does not report the analyses needed to assess them.

Another lesson is the importance of reporting uncertainty and analysis populations. The record names a continuous endpoint and a mean with standard deviation, but does not provide the numerical summary or the participants contributing to it. Without estimates, dispersion, and information about missing observations, readers cannot assess how precise or representative a result would be. A count of enrolled participants cannot substitute for those details.

Finally, planning assumptions should be kept separate from the study’s actual design. The described planning framework uses equal allocation between two arms, while this study is listed as single-group. This difference illustrates why a planning illustration should not be mistaken for an original protocol, observed power, or evidence of a clinical effect. The record’s value is in identifying the planned question and the limits of the information available, not in establishing imaging performance.

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 a reason for the terminated status, so the implications of termination for recruitment, follow-up, data completeness, or study conduct cannot be determined. It lists enrollment of 6, but does not report participant characteristics, eligibility details beyond breast cancer and neoadjuvant chemotherapy, or the number with usable measurements at each planned visit.

The primary endpoint is described at baseline, whereas the principal scientific aims concern early response during treatment and prediction against pathology or clinical outcome. No results for the repeated imaging measures, pathology, or clinical outcomes are reported. The record also does not provide the operational definition of response, the timing of surgical pathology assessment, or criteria for judging predictive performance.

There is no randomized control group, and grayscale ultrasound is part of the imaging procedure rather than a separately allocated comparator arm. Although several comparisons are described as objectives, no comparative estimates or analysis methods are posted. The registry does not report how missing measurements, timing deviations, multiple outcomes, or the analysis population were handled. These omissions prevent assessment of potential bias, uncertainty, and the consistency of any findings.

The safety listing provides aggregate counts but no event narratives or further context. The record’s off-label use description is informative about the study procedure, but does not substitute for detailed safety results. These limitations are specific to the information reported for this study and should be distinguished from conclusions about the technology or its use in other settings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Breast VCEUS to Evaluate Early Response to Neoadjuvant Chemotherapy — NCT01817374.
• Registry record last updated 2018-01-26; status last verified 2018-01.
• Results first posted 2017-11-21.
• 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

NCT01817374 is a terminated, single-group pilot study sponsored by the University of Alabama at Birmingham. The registry records a start of 2015-06, primary completion of 2016-07, and enrollment of 6. The study evaluated quantitative VCEUS imaging alongside grayscale ultrasound in patients with breast cancer receiving neoadjuvant chemotherapy.

The primary outcome is baseline grayscale ultrasound size along the longest axis, summarized as a mean with standard deviation and measured in millimeters. The record lists nine outcome measures and zero analyses. It does not report the primary endpoint result, response-related estimates, analysis methods, or reason for termination. The safety listing records zero affected participants for serious and other adverse events, with 6 at risk in each category and deaths recorded as 0. The registry therefore documents the study’s design and aims, but does not provide results that answer its central imaging-prediction questions.