Linear Energy Transfer (LET)-Optimized Intensity Modulated Proton Therapy (IMPT) as a Component of Definitive Chemoradiation for Newly Diagnosed Squamous Cell Carcinoma of the Anal Canal: a Feasibility Trial: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Linear Energy Transfer (LET)-Optimized Intensity Modulated Proton Therapy (IMPT) as a Component of Definitive Chemoradiation for Newly Diagnosed Squamous Cell Carcinoma of the Anal Canal: a Feasibility Trial (NCT03690921), a na phase 2 study. The primary outcome is Acute Toxicity.

2. Clinical Question

3. Trial Design

This was a phase II, single-group feasibility trial sponsored by M.D. Anderson Cancer Center. The registry lists the trial as completed, with enrollment of 8 participants. It began on 2018-11-08 and had a primary completion date of 2022-06-03. The record lists no allocation because participants were not assigned between comparative arms, and masking was none.

All participants were in the treatment group receiving LET-IMPT and chemotherapy. Radiation was described as delivered 5 times per week for 5-6 weeks. Cisplatin and fluorouracil were given intravenously weekly for up to 6 weeks, in the absence of disease progression or unacceptable toxicity. Quality-of-life assessment and questionnaire administration were also listed as interventions.

A single-group design can describe what happened among participants who received the regimen, but does not estimate a treatment contrast against a concurrent control group. The record therefore cannot establish whether outcomes differ from those under another approach. The trial's feasibility framing is reflected in its title, but specific feasibility criteria or a formal feasibility endpoint are not reported in the registry record.

The listed secondary outcomes include complete response at 12 weeks and 24 weeks, local progression-free survival at 24 months, distant metastasis-free survival at 24 months, and overall survival at 24 months. The record lists six outcome measures overall. Results for these outcomes are not included in the information available 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: There were no enrolled patients excluded prior to assignment to arms or groups.

Overall Study

Analysis population for the primary outcome, as defined in the registry: All patients with 12 week follow up.

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 Acute Toxicity, measured over Acute physician reported toxicity from start of treatment 12 weeks post-treatment.

The primary endpoint is acute toxicity, measured as the number of participants with physician-reported acute G3+ GI, GU, and heme toxicities. Its timeframe runs from the start of treatment through 12 weeks after treatment. The stated population is all patients with 12 week follow up. The registry characterizes the measure as a participant count, with a description that also refers to a percentage.

A toxicity endpoint is used to characterize treatment-related harms over a defined observation period. Physician-reported grading provides a structured way to classify the severity of reported events; the G3+ threshold identifies the toxicity categories specified by the trial. Counts describe how many participants met the endpoint, while percentages relate those counts to an appropriate denominator. The denominator matters: the primary endpoint population is defined by having 12 week follow up, but the number of participants meeting that population definition is not reported in the registry record.

The endpoint result itself is also not reported in the registry record. Consequently, this description identifies what the endpoint was designed to measure, not the frequency or severity observed in the trial. No inference about toxicity incidence from the endpoint can be made from its definition alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What kind of outcome is the primary endpoint?

General: A participant-count endpoint is a binary outcome at the participant level. Each participant either meets the prespecified endpoint definition during the observation period or does not. The registry describes acute toxicity as a count, while also stating that the measure is a number and percentage of patients with specified physician-reported toxicities. A count is interpreted alongside its denominator; a percentage expresses the count relative to that denominator. Both depend on a clear endpoint definition and consistent ascertainment.

For this trial, the endpoint names G3+ GI, GU, and heme toxicities, and sets the observation window from treatment start through 12 weeks post-treatment. The stated population is all patients with 12 week follow up. The registry does not provide the number meeting that follow-up requirement, the number with endpoint events, or an endpoint estimate. Therefore, an event proportion cannot be reconstructed from the record.

Why do denominators and follow-up matter?

General: A denominator should correspond to the population eligible for the outcome analysis. If participants lack sufficient follow-up, their endpoint status may be unknown rather than event-free. Treating missing status as absence of an event can misrepresent risk. An analysis may instead define a follow-up population, use an explicit missing-data method, or report how many outcomes are unavailable. Which approach is appropriate depends on the endpoint and the missingness process.

The registry identifies the primary endpoint population as patients with 12 week follow up, but does not describe how incomplete follow-up would be handled or report the population count. It also does not report the analysis population for the secondary outcomes. These omissions limit assessment of who contributed to each outcome and whether the analyzed groups differed from the enrolled group.

How should uncertainty be understood?

General: An estimate describes the observed data; a confidence interval describes the range of values compatible with those data under the assumptions of the method. Wider intervals indicate less precision. With a small participant count, event estimates can be imprecise, especially when the event is uncommon. A point estimate alone does not communicate that uncertainty. The registry record does not report a primary endpoint estimate, confidence interval, or statistical test result, so there is no endpoint uncertainty estimate to interpret.

A p-value, when reported, addresses how compatible the data are with a specified statistical model and null hypothesis. It is not the probability that a treatment is effective, nor does it measure clinical importance. No p-value or primary endpoint hypothesis test is reported in the registry record. The statistical analysis plan, including the intended method for the primary endpoint, is not reported in the registry record.

What can a single-group design estimate?

General: In a single-group study, outcome summaries characterize the participants who received the study regimen. Without a concurrent comparator, the study does not directly estimate a between-group contrast. Changes over time or observed event frequencies can reflect treatment, disease characteristics, other care, or chance. Randomized allocation is one way to balance factors between groups, but this trial does not have randomized comparative arms.

The registry lists allocation as not applicable, masking as none, and the model as single group. Accordingly, findings from this design would need to be read as descriptive of the enrolled participants rather than as a randomized estimate of comparative benefit or harm. The record does not report an adjusted analysis or a causal analysis.

How do the secondary outcomes differ?

The record lists complete response at 12 weeks and 24 weeks, as well as local progression-free survival, distant metastasis-free survival, and overall survival at 24 months. Response outcomes classify a participant according to whether the specified response criterion is met at a stated assessment time. Time-to-event outcomes concern the timing of an event and require clear definitions of the event, follow-up, and censoring. General: Censoring occurs when the event time is not observed during available follow-up; its handling affects interpretation of time-to-event estimates.

The registry record does not report event definitions beyond the outcome names, analysis methods, estimates, or uncertainty measures for these outcomes. It also does not report how repeated assessment times or multiple outcomes were handled analytically. Those details should not be inferred from the outcome labels.

What is not documented?

The statistical analysis plan, sample-size justification, interim analyses, and methods for missing outcome data are not reported in the registry record. The record's sample-size assumptions describe planning illustrations based on an observed effect, but no resulting planning values are present in the registry record for this analysis. Such illustrations are not observed power, and they do not substitute for the trial's own design justification. The absence of a documented method means it is not possible to verify which statistical procedures were prespecified or how they were applied.

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("IMPT for Anal Cancer (Single Arm Trial)")
n      <- c(8)
events <- c(2)
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  IMPT for Anal Cancer (Single Arm Trial)  8  2  25.0  3.2  65.1  7.1  59.1  7.5  60.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures, including acute toxicity as the primary outcome and response, progression-free, metastasis-free, and overall survival outcomes. When a study examines multiple outcomes, the chance of at least one apparently notable result can increase if each is assessed separately. General: A multiplicity strategy can define which outcomes are confirmatory, adjust the interpretation of tests, or treat results as exploratory. The choice depends on the study objectives and analysis plan.

Multiplicity handling is not reported in the registry record. The record does not describe a hierarchy among the secondary outcomes, adjustment of significance levels, or a plan for interpreting multiple tests. Since results and test statistics are not reported in the registry record, no assessment of multiplicity-adjusted or unadjusted findings is possible.

Missing-data methods are also not reported in the registry record. The primary endpoint population is defined as all patients with 12 week follow up, but the number meeting this definition and the handling of participants without that follow-up are not stated. Follow-up and missingness details for the secondary outcomes are likewise not reported.

The analysis populations are not fully described. The record does not state whether outcomes were analyzed for all enrolled participants, only participants who began treatment, or another defined group. These distinctions matter because the group contributing to an outcome may differ from the enrollment group. No assumptions about missing outcomes, exclusions, or analysis populations can be made from the registry record.

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 non-serious adverse event terms

The registry safety record lists 8 participants at risk for serious adverse events and 0 affected. It lists 8 participants at risk for other adverse events and 8 affected. It also records 1 death. These counts describe the safety fields in the registry; they do not supply the missing primary endpoint result.

The primary endpoint is specifically the number and percentage of participants with physician-reported acute G3+ GI, GU, and heme toxicities through 12 weeks after treatment. The safety fields are broader categories and do not establish how many participants met that endpoint. In particular, the count for other adverse events should not be treated as the number with the specified acute toxicity endpoint.

The record does not report the types, timing, duration, severity, or attribution of the other adverse events, nor does it state the cause or timing of the death. The serious-event count should not be interpreted as proof that no serious event occurred outside the reported record or observation period. These aggregate safety counts offer limited information and do not support conclusions about comparative safety, given the single-group design and absence of a comparator.

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

The registry record establishes that a completed phase II, single-group trial enrolled 8 participants to receive LET-IMPT with cisplatin and fluorouracil. It specifies acute physician-reported toxicity as the primary endpoint and gives the follow-up window and endpoint population. It also lists response and survival outcomes and reports aggregate adverse-event counts.

It does not report the result for acute toxicity, or results for the secondary outcomes. The posted safety counts cannot replace those outcome results because they refer to broad serious and other adverse-event categories, not specifically to the defined primary endpoint. The registry record also does not provide enough event detail to interpret the listed death.

These data do not establish whether the regimen is more or less effective or safe than another treatment. There is no comparative group, and no randomized contrast. The record also does not provide outcome estimates with uncertainty measures. A small enrollment makes precision an important consideration in general, but an actual precision estimate cannot be stated without reported endpoint results.

More broadly, absence of a result in the registry record is not evidence that the outcome had no events or that no analysis was performed. It means the outcome result is not reported in the record. The trial's title identifies feasibility as its purpose, but the record does not state explicit feasibility criteria or results. Interpretation should therefore remain limited to the documented design, endpoint definitions, and available safety counts.

14. Why This Trial Matters Statistically

This trial raises several statistical issues relevant to interpreting early clinical research. Its single-group structure means that outcome summaries, if available, would describe enrolled participants receiving the regimen rather than estimate a randomized treatment contrast. Recognizing that distinction prevents descriptive results from being treated as evidence of comparative effects.

The primary endpoint is a defined participant-level toxicity measure with a specified time window and follow-up population. That level of definition is important: an event count is meaningful only when the event criteria, observation period, and denominator are clear. The record identifies these elements in part, while leaving the endpoint result and the size of the 12 week follow-up population unreported.

The record also illustrates why broad safety summaries and a prespecified endpoint are not interchangeable. Serious and other adverse-event categories provide a different view from the specified G3+ GI, GU, and heme toxicity outcome. Without event-level details, readers should avoid inferring that one measure answers the question posed by another.

Finally, small enrollment and unreported analysis details make precision, missingness, and multiplicity especially relevant questions. The statistical analysis plan and methods for missing data and multiple outcomes are not reported in the registry record. Reporting endpoint estimates with uncertainty and explaining analysis populations would help readers assess what the observed data can support. These are general reporting considerations, not claims about analyses that were or were not conducted.

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 provides limited outcome information for this trial. It describes the primary endpoint but does not report its result, and it does not report results for the listed secondary outcomes. Consequently, the primary toxicity frequency, response findings, and survival estimates cannot be assessed from this record.

Enrollment was 8, and the trial had a single group with no comparator. This limits both precision and the ability to separate outcomes associated with the regimen from other influences. The registry does not report confidence intervals or other uncertainty measures for the endpoints.

The primary endpoint population is defined as all patients with 12 week follow up, but the number of participants meeting that definition and the handling of missing follow-up are not reported in the registry record. The analysis populations for other outcomes are also not stated. The statistical analysis plan, sample-size justification, interim analyses, and multiplicity methods are not reported.

Safety reporting is aggregate. The record gives counts for serious and other adverse events and deaths, but does not report event descriptions, severity details beyond the category fields, timing, duration, or attribution. The acute toxicity endpoint has a separate, narrower definition, and its result is unavailable. The feasibility purpose is present in the trial title, but criteria and feasibility results are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Linear Energy Transfer (LET)-Optimized Intensity Modulated Proton Therapy (IMPT) as a Component of Definitive Chemoradiation for Newly Diagnosed Squamous Cell Carcinoma of the Anal Canal: a Feasibility Trial — NCT03690921.
• Registry record last updated 2023-06-29; status last verified 2023-06.
• Results first posted 2023-06-29.
• 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

NCT03690921 is a completed phase II, single-group feasibility trial sponsored by M.D. Anderson Cancer Center. It enrolled 8 participants with newly diagnosed stage I-III anal canal squamous cell carcinoma and evaluated LET-IMPT with cisplatin and fluorouracil. The registry lists no masking and no allocation to comparative arms.

The primary endpoint was acute physician-reported G3+ GI, GU, and heme toxicity from treatment start through 12 weeks post-treatment, among patients with 12 week follow up. The registry record does not report the endpoint result or results for the listed secondary outcomes. Safety fields list 0 affected among 8 at risk for serious adverse events, 8 affected among 8 at risk for other adverse events, and 1 death. The record does not report the event details needed for further interpretation.