Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours (NCT02181075), a non-randomized phase 1 study. The primary outcome is Concentration of Total Intratumoral Doxorubicin in Liver Tumour (Biopsies) Following Targeted Release of Doxorubicin From ThermoDox® ('Drug') Using Mild Hyperthermia Generated Non-invasively by Focused Ultrasound (FUS).

2. Clinical Question

The study asked whether focused ultrasound (FUS), used to generate mild hyperthermia in a target liver tumour after administration of ThermoDox® (LTLD), could increase the concentration of doxorubicin measured in tumour tissue. It was a proof-of-concept investigation of targeted drug release, rather than a randomized comparison of treatment strategies. The registry describes adult patients with incurable, confirmed primary or secondary hepatic tumours receiving a single cycle of LTLD and ultrasound-mediated hyperthermia directed at a single target tumour.

The biological rationale was that mild hyperthermia generated at the tumour could trigger release of doxorubicin from the specially formulated liposomal drug. The endpoint included both released and unreleased doxorubicin, so it measured total drug in the sampled tissue rather than released drug alone. The registry record does not report the primary endpoint estimate or its uncertainty. The study therefore poses a measurable tissue-delivery question, but the posted information does not establish the magnitude or precision of any change.

3. Trial Design

This was a Phase 1, non-randomized, unmasked, parallel-model study sponsored by the University of Oxford. The registry lists enrollment of 10 and a completed status. The study began in 2014-07, with primary completion in 2017-03. Its stated purpose was proof of concept: to investigate the feasibility of using FUS-mediated mild hyperthermia to target release of doxorubicin from LTLD in people with primary or secondary liver tumours.

The registry divides the study into Part I and Part II. In Part I, the listed sequence included a pre-LTLD biopsy, LTLD, a post-LTLD biopsy, FUS of the target tumour, thermometry, and a post-LTLD-plus-FUS biopsy. In Part II, the listed procedures included LTLD, FUS, and a post-LTLD biopsy. The record says Part II could open after a minimum of 5 Part I cases, subject to Trial Management Group approval, and could then run in parallel with Part I. The fuller descriptions of the parts are truncated in the registry text, so additional procedural detail is not reported in the registry record.

These parts should not be read as randomized treatment and control arms. Allocation was non-randomized, and the registry explicitly cautions that the arms are not a like-for-like control comparison. The primary endpoint concerns tissue drug concentration, not a direct randomized comparison of clinical outcomes. The registry describes a single cycle of LTLD followed by ultrasound-mediated hyperthermia to a target tumour. It does not report a separate untreated control group, a randomization procedure, or masking of participants or investigators.

The primary endpoint is a continuous measure expressed as micrograms of total doxorubicin per gram of tumour biopsy. The stated timeframe compares a post-intervention sample on Day 1 with a pre-intervention sample on Day 1. The endpoint description also says that doxorubicin concentration was evaluated in samples after LTLD and after LTLD plus FUS. The exact mapping of all biopsy time points to the stated pre- and post-intervention comparison is not further explained in the registry 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.

Before assignment: 10 patients were recruited (6 to Part I of the study and 4 to Part II of the study). Patients required at least one liver tumour accessible to ultrasound. Full screening criteria are available from ClinicalTrials.gov or the published protocol summary, both detailed in the References section.

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 Concentration of Total Intratumoral Doxorubicin in Liver Tumour (Biopsies) Following Targeted Release of Doxorubicin From ThermoDox® ('Drug') Using Mild Hyperthermia Generated Non-invasively by Focused Ultrasound (FUS), measured over Post-intervention sample (Day 1) compared to pre-intervention sample (Day 1).

The primary endpoint is the concentration of total intratumoral doxorubicin in liver tumour biopsy tissue, expressed in ug/g of total doxorubicin(tumour biopsy). The registry specifies a mean and standard deviation as the summary measures. The endpoint description says the laboratory assay measured total doxorubicin, including both released and unreleased forms, in tumour biopsy sections. Samples were assessed after LTLD and after LTLD plus FUS.

This tissue measure was selected to address the study’s drug-delivery question: whether adding FUS-mediated mild hyperthermia was associated with a higher concentration of doxorubicin in the targeted tumour. A biopsy provides a direct sample of tumour tissue, while the assay quantifies drug in that sample. The endpoint is therefore a pharmacologic and feasibility measure, not a measure of tumour response, survival, or comparative clinical benefit.

As a general statistical point, a mean describes the center of a set of measurements, while a standard deviation describes how spread out individual measurements are around that mean. A difference in means can summarize a within-person or between-sample contrast, but its interpretation depends on how samples were paired, which participants contributed measurements, and how missing samples were handled. Those details are not reported in the registry record.

The registry gives the assay method as High Performance Liquid Chromatography using a validated assay in a Good Clinical Practice Laboratory. Samples were frozen at -80^oC for later analysis rather than analyzed the same day. The endpoint estimate, standard deviation, participant-level data, and confidence interval are not reported in the registry record, so the size and precision of the measured tissue concentrations cannot be assessed from the posted results described in the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Interpreting the endpoint requires separating the measurement, its summary, and the comparison of interest. The measurement is total doxorubicin concentration in a tumour biopsy. The registry says the assay included both released and unreleased forms of the drug. The summary is a mean with a standard deviation. The comparison concerns samples collected at the specified procedural stages, including after LTLD and after LTLD plus FUS. The registry lists a post-intervention versus pre-intervention timeframe on Day 1, but does not fully explain how those labels correspond to each biopsy in the procedural sequence.

What a mean and standard deviation describe

General statistical explanation: a mean is an average across measured observations. It is useful for describing the center of a continuous outcome, but it can be affected by extreme measurements. A standard deviation describes the spread of observations around the mean. It is not the uncertainty in the mean itself: uncertainty also depends on the number of observations and the analysis design. The registry record does not report the endpoint means, standard deviations, or the number of evaluable samples at each time point, so these summaries cannot be interpreted numerically.

For a tissue concentration endpoint, variation may arise from differences between participants and from differences between sampled tumour regions. A biopsy represents the sampled tissue, not necessarily every region of a tumour. The record describes tumour biopsies and a validated laboratory assay, but does not report replicate measurements, the number or location of cores, or procedures for combining multiple samples. These features affect how closely the measured value represents a participant’s tumour as a whole.

Within-participant comparisons

General statistical explanation: when two measurements come from the same participant, their relationship can be important. A paired analysis evaluates each participant’s change and accounts for the fact that measurements from the same person may be more alike than measurements from different people. An unpaired analysis treats measurements as independent. The registry’s biopsy sequence makes a within-participant comparison plausible, but the statistical analysis method and pairing strategy are not reported in the registry record. It would therefore be inappropriate to assume a particular test or to reconstruct a paired estimate.

Biopsy measurements taken at different stages also differ in time and procedure. A change between samples may reflect the intervention, but could also be influenced by sampling variation, tissue heterogeneity, or other differences in collection and processing. The stated laboratory method and sample storage conditions describe how the assay was conducted; they do not by themselves resolve those sources of variation.

Uncertainty and confidence intervals

General statistical explanation: a confidence interval gives a range of values compatible with the data and the specified statistical model, reflecting sampling uncertainty. A narrow interval generally indicates greater precision than a wide interval, although precision is not the same as clinical importance or freedom from bias. The registry record does not report a confidence interval or other uncertainty interval for the primary endpoint. Without one, the precision of the estimated concentration or contrast cannot be assessed from the posted record.

A p-value, if reported, would address compatibility between the data and a specified null model, under the assumptions of the analysis. It would not measure the probability that the study hypothesis is true or quantify the size of an effect. The registry record does not report a primary endpoint p-value or a detailed statistical analysis plan. No significance conclusion can be inferred from the study’s objective or its completed status.

Planning illustrations and observed results

General statistical explanation: sample-size illustrations based on an observed effect ask how many participants per arm might be needed to detect a chosen fraction of that effect under stated assumptions. They are planning exercises, not evidence that a study had a particular probability of finding a result, and they are not observed power. In this case, the planning assumptions described in the record are two-sided significance level 0.05, equal allocation between two arms, and a normal approximation. The illustration uses a stated fraction of the observed effect. The record distinguishes total events for time-to-event illustrations from participants per arm for other outcomes.

Those assumptions do not describe the study’s own design justification. This trial was non-randomized, and the registry record does not report a sample-size justification for the trial. No numerical sample-size illustration or observed primary endpoint effect is reported in the registry record. Thus, the stated planning framework should not be mistaken for the actual enrollment rationale, a randomized design, or evidence about the precision of this study’s findings.

Interpretation in context

General statistical explanation: statistical methods depend on the structure of the data and the question being asked. A continuous concentration outcome, repeated biopsies, multiple study parts, and safety outcomes may call for different summaries and analyses. The registry reports six outcome measures and one analysis, but does not describe a complete analysis plan or the populations used for each analysis. The endpoint estimate, its uncertainty, and the details needed to assess the analysis are not reported in the registry record. The main methodological conclusion is therefore about interpretability: the endpoint is clearly described as a tissue concentration measure, while the numerical evidence and several analysis details needed to evaluate it are unavailable in the record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures and one analysis. The primary measure concerns total intratumoral doxorubicin concentration. Listed secondary outcomes include satisfactory hyperthermia in the target liver tumour across participant body mass indices and tumour locations in Part I, persistence of a cell viability stain after LTLD plus FUS, and patients with significant grade 3-5 adverse events deemed related to LTLD or to the FUS procedure. The full set of outcome definitions and the statistical analysis plan are not reported in the registry record.

Multiplicity arises when several outcomes, time points, subgroups, or analyses are considered. General statistical explanation: the more statistical questions examined, the greater the chance that at least one result may appear notable by chance if no adjustment or prespecified hierarchy is used. Whether adjustment is needed and how it should be done depend on the study’s aims and analysis plan. The registry record does not report a multiplicity strategy, a hierarchy among secondary outcomes, or whether any adjustment was made. The number of analyses listed does not establish how all planned comparisons were handled.

The record does not report missing-data counts for the primary endpoint, reasons for missing biopsies, or methods for handling missing measurements. It also does not report whether the primary analysis used all enrolled participants, only participants with evaluable paired samples, or another analysis population. These details matter because participants who contribute measurements may differ from those who do not, and because a paired comparison requires information from the relevant sampling stages.

General statistical explanation: complete-case analysis, imputation, and model-based approaches rely on different assumptions about why data are missing. Without the missingness pattern and the analysis method, the effect of missing measurements on the estimate cannot be assessed. The registry record also does not describe a prespecified statistical plan, interim analyses, or sensitivity analyses. These omissions limit assessment of how robust the reported endpoint would be to analysis choices, independently of the fact that the primary numerical result is not reported.

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: neutropenia (50.0%), confusion (25.0%).

The registry reports safety figures separately for Part I and Part II. In Part I, 6 participants were listed as at risk for serious adverse events and 3 as affected; 6 were listed as at risk for other adverse events and 6 as affected. In Part II, 4 participants were listed as at risk for serious adverse events and 3 as affected; 4 were listed as at risk for other adverse events and 4 as affected. Deaths are listed as 0 in each part.

The registry lists neutropenia at 50.0% and confusion at 25.0% among the top serious adverse event terms. The denominator and event counts behind those term percentages are not reported in the registry record. The terms should therefore be read as registry-listed summaries, not as a complete account of all event types or a basis for reconstructing participant-level counts.

These figures are descriptive counts in small, non-randomized study parts. The parts had different listed procedures and were not like-for-like control arms, so their counts do not support a comparative safety estimate. The aggregate figures also do not establish causation. Although a secondary outcome concerns significant grade 3-5 adverse events deemed related to LTLD or FUS, the safety figures do not provide the attribution details for each event. The registry record does not report further information on event timing, duration, management, or participant-level overlap between event categories.

General statistical explanation: adverse-event counts can help describe what was recorded during a study, but interpretation depends on definitions, follow-up, attribution, and the number of people observed. Counts from a small study can be unstable and should not be treated as precise estimates of event frequency in a wider population. The listed deaths and adverse-event figures are registry summaries, not a complete clinical safety assessment.

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

The trial’s central contribution is its focus on measuring doxorubicin directly in biopsies from a target liver tumour after LTLD and FUS. The registry gives a rationale for that measurement: mild hyperthermia generated by focused ultrasound was intended to trigger targeted drug release. It also specifies an assay for total doxorubicin, including released and unreleased forms. This establishes what the investigators set out to measure, but the primary concentration results are not reported in the registry record.

Accordingly, the record does not allow readers to determine whether measured concentrations were higher after FUS, how large any difference was, or how variable the measurements were. It also does not show whether the planned tissue comparison was sufficiently precise to distinguish a consistent pattern from sampling variation. Without the numerical estimate, its uncertainty, and the number of evaluable samples, no conclusion about the observed degree of drug delivery can be drawn from the posted record.

The design does not test whether this approach improves tumour control, survival, symptoms, or any other clinical outcome. Its primary endpoint is a tissue concentration, and its stated objective is proof of concept and feasibility. A change in a drug concentration would be a pharmacologic observation; it would not by itself demonstrate a clinical benefit. Conversely, absence of a reported result is not evidence that the intervention had no effect.

The study also does not provide a randomized comparison of FUS against no FUS. The registry identifies a non-randomized design and cautions that Part I and Part II are not like-for-like control arms. The parts’ procedures differ, and the record does not report the statistical methods needed to assess comparisons across biopsy stages or study parts. Any causal claim would therefore go beyond the information reported.

General statistical explanation: a proof-of-concept study can inform whether a measurement strategy is feasible and can motivate further research, while leaving important questions about effect size, variability, and clinical outcomes unresolved. In this case, the registry record states the intended tissue endpoint and reports aggregate safety counts, but does not report the primary endpoint result or enough analysis detail to assess its precision. The appropriate interpretation is limited to the study’s design and the information actually recorded.

13. Why This Trial Matters Statistically

This trial is statistically distinctive because it frames drug delivery as a measurable tissue endpoint rather than relying only on a clinical outcome. Biopsies were planned at stages around LTLD and FUS, allowing the investigators to examine total doxorubicin in the targeted tumour. Such a measure can help characterize whether a delivery strategy produces a detectable pharmacologic signal. The registry also describes thermometry, which relates to the study’s aim of generating hyperthermia in the target tumour.

The design illustrates why the structure of a comparison matters. Samples collected at different times from the same participant are not automatically equivalent to randomized treatment and control groups. Their analysis depends on pairing, missing measurements, sampling procedures, and the handling of within-tumour variation. The registry record does not report these analysis details, and it expressly cautions that the study parts are not like-for-like controls. That distinction is essential when interpreting a mechanistic study.

The record also highlights the difference between a feasibility question and a clinical-effectiveness question. It describes a Phase 1 proof-of-concept study with enrollment of 10 and a single-cycle intervention, while its primary endpoint is a concentration measured in biopsy tissue. The endpoint can address drug presence in sampled tissue, but it cannot alone answer whether the intervention changes patient outcomes.

Finally, statistical interpretation depends on reported estimates, not just a well-defined objective. Means and standard deviations are named as the endpoint summaries, but their values and an uncertainty interval are not reported in the registry record. This prevents readers from judging the observed signal’s size and precision. The study remains a useful example of how carefully defined mechanistic endpoints can be clinically motivated while requiring transparent reporting of the analysis and results for statistical evaluation.

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 direct limitation of the registry record is that it does not report the primary endpoint estimate, its standard deviation, or an uncertainty interval. As a result, the central tissue-concentration question cannot be answered from the posted information. The record also does not report the number of participants with evaluable samples at each time point, the sample-level data, or the statistical method used to compare measurements.

The registry describes a non-randomized design and explicitly warns that the study parts are not a like-for-like control comparison. The parts also have different listed procedures. This prevents interpreting Part I and Part II as randomized arms and limits what can be learned from any unadjusted contrast between them. The record does not report a control group that received LTLD without FUS under otherwise comparable conditions.

The endpoint is based on biopsy tissue, and the registry does not report the number or location of biopsy cores, how multiple tissue samples were combined, or how tumour heterogeneity was addressed. The assay description and storage information are useful, but do not establish how representative each biopsy was of the whole target tumour. The record also describes total doxorubicin, including released and unreleased forms, so it does not isolate the released fraction.

Further limitations include the absence of reported missing-data methods, analysis populations, multiplicity procedures, interim-analysis information, and a detailed statistical analysis plan. The record does not state the trial’s sample-size justification. Its planning assumptions concern an illustration based on an observed effect, not the design rationale for this non-randomized study. The aggregate safety information does not provide detailed event attribution or participant-level context. These limitations constrain assessment of precision, robustness, generalizability, and causal interpretation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Targeted Chemotherapy Using Focused Ultrasound for Liver Tumours — NCT02181075.
• Registry record last updated 2019-07-22; status last verified 2018-11.
• Results first posted 2019-06-24.
• 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

NCT02181075 is a completed Phase 1, non-randomized, unmasked, parallel-model proof-of-concept study sponsored by the University of Oxford. The registry lists enrollment of 10, a start in 2014-07, and primary completion in 2017-03. The study investigated ThermoDox® (LTLD) with focused ultrasound-mediated hyperthermia in adults with incurable, confirmed primary or secondary liver tumours.

The primary endpoint was mean total intratumoral doxorubicin concentration in biopsy tissue, with standard deviation as the dispersion measure. The record describes samples after LTLD and after LTLD plus FUS, but does not report the numerical endpoint result, its uncertainty, or the analysis method. Part I and Part II had different listed procedures and were not like-for-like control arms.

Registry safety summaries list serious and other adverse events by study part and deaths as 0 in both parts. The primary endpoint results, missing-data methods, analysis populations, multiplicity strategy, and trial sample-size justification are not reported in the registry record.