Preoperative CRT With Temozolomide Plus Capecitabine in Rectal Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Preoperative CRT With Temozolomide Plus Capecitabine in Rectal Cancer (NCT01781403), a na phase 1 study. The primary outcome is Maximum Tolerated Dose (MTD).

2. Clinical Question

The study’s stated rationale concerns the combination of temozolomide with preoperative radiation and capecitabine. The registry summary also discusses MGMT promoter hypermethylation or low expression as a possible predictive biomarker rationale. Whether that biomarker was measured, and any biomarker findings, are not reported in the registry record. A secondary outcome is pathological complete response, but its result is not reported in the registry record.

This is a dose-finding question, rather than a comparative question about whether one regimen performs better than another. The registry does not identify a concurrent standard-treatment group or a randomized comparison. Accordingly, the central information sought is the tolerability threshold across tested temozolomide dose levels in the combination, not an estimate of treatment effect relative to an alternative.

3. Trial Design

The registry lists this study as phase I, completed, and single group. Enrollment is listed as 22. Allocation is marked not applicable, and masking is listed as none. These features indicate that the registry does not describe a randomized, masked comparison between treatment groups. It instead lists dose-level groups for the combination regimen.

The treatment is described as preoperative chemoradiation with capecitabine, temozolomide, and radiotherapy. The radiotherapy description specifies a total dose of 50.4 Gy, with 1.8 Gy administered daily on 5 days of each week, consisting of 45 Gy to the whole pelvis followed by a 5.4 Gy boost to the primary tumor. The registry says capecitabine doses and schedules were fixed and temozolomide was the drug varied, but the available regimen description is truncated. Complete dosing details are therefore not reported in the registry record.

The safety listing contains Dose Level 1, Dose Level 2, and Dose Level 3/Recommended Dose. Their listed at-risk counts are 2, 2, and 18, respectively. Those groups describe the registry’s safety reporting and should not be interpreted as independently randomized arms. The specific dose amounts, rules for moving between levels, and the process used to select the recommended dose are not reported in the registry record.

The primary outcome is maximum tolerated dose, assessed over 5-6 weeks during study treatment. The registry also lists pathological complete response as a secondary outcome. It reports six outcome measures, but does not report outcome analyses in the record; the number of analyses listed is 0. Details of eligibility, follow-up beyond the primary outcome timeframe, stopping rules, interim reviews, and the statistical analysis plan are not reported 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.

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 Maximum Tolerated Dose (MTD), measured over 5-6 weeks during study treatment.

The primary endpoint is maximum tolerated dose (MTD), expressed in mg/m^2. The registry defines it as the maximum dose level among the temozolomide doses tested with capecitabine and radiation in which the incidence proportion of dose-limiting toxicity exceeds 30%. The stated assessment timeframe is 5-6 weeks during study treatment. The registry does not report the observed MTD result, the dose amounts tested, or the dose-limiting toxicity criteria.

As a general statistical concept, an MTD endpoint is used in early-phase dose-finding research to characterize a dose in relation to observed treatment-limiting toxicity under a specified regimen and assessment period. It is not the same as an estimate of comparative efficacy: this single-group study has no listed control group, and the primary endpoint is about dose and toxicity rather than a between-group treatment effect. Interpretation depends on how toxicity is defined, how it is assessed, and how dose levels are selected. Those operational details are not reported in the registry record.

The endpoint’s definition refers to a threshold of more than 30% for the incidence proportion. That definition alone does not establish which tested dose met the rule or whether the study identified an MTD. Because the outcome value is absent, the registry record does not support naming a selected MTD or judging the precision of such an estimate. Pathological complete response is listed as a secondary outcome, but its result and analysis are also not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a dose-finding endpoint represent?

In general, a dose-finding study examines how treatment-related toxicity varies across dose levels and uses a prespecified rule to guide selection of a dose for further study. The registry defines this study’s MTD in terms of the dose-limiting toxicity incidence proportion and a threshold exceeding 30%. The dose levels listed are Dose Level 1, Dose Level 2, and Dose Level 3/Recommended Dose. The dose amounts and the exact operational procedure used to assign or escalate doses are not reported in the registry record. As a result, the endpoint definition can be described, but the dose-finding procedure cannot be reconstructed.

How should an incidence proportion be read?

As a general statistical concept, an incidence proportion is the number of participants meeting an event definition divided by the number of participants at risk over a specified period. It describes how often the event was observed in that defined group and timeframe. The registry’s safety entries list counts of participants affected and at risk, but do not identify the events composing the “other” category. Nor does the record provide the dose-limiting toxicity criteria needed to connect the adverse-event listing directly to the primary MTD rule. The safety counts should therefore not be treated as a substitute for the missing MTD result.

What does a confidence interval add?

In general, a confidence interval expresses the uncertainty around an estimate under a specified statistical method. It is useful because a point estimate alone does not show how precisely a quantity has been estimated. For a dose-finding result, uncertainty depends on the underlying toxicity observations, dose allocation process, endpoint definition, and analysis method. No confidence interval for MTD or for the listed adverse-event counts is reported in the registry record. Without the outcome results and analysis details, the precision of the primary estimate cannot be assessed.

Why do small groups matter?

In general, estimates based on small groups tend to be sensitive to individual observations and can have substantial uncertainty. The registry lists 2 participants at risk in each of the first two dose-level groups and 18 at risk in the Dose Level 3/Recommended Dose group. These counts describe the reported safety groups; they do not show by themselves how dose selection was conducted or whether the groups are comparable. The unequal group sizes are consistent with a dose-finding context, but the registry does not report the rationale or allocation procedure. There is no basis in the record for treating these groups as control and intervention arms.

What can be inferred from the safety counts?

The serious adverse event entries are zero in each listed group, with the corresponding at-risk counts shown in the registry. The “other” adverse event entries list every at-risk participant as affected. These are counts, not estimates of a comparative treatment effect. The record does not include named event terms, event severity breakdowns for the non-serious category, exposure-adjusted rates, or uncertainty estimates. General statistical interpretation cautions that a zero observed count is not proof of zero underlying risk, especially when the number observed is limited. It also matters that the registry’s serious and other adverse event categories may have different definitions; full definitions are not reported in the registry record.

What is the role of a sample-size calculation?

As a general concept, a sample-size calculation is a planning exercise based on assumptions about a target effect, variability, significance level, allocation, and analysis method. It does not show what a completed study observed and should not be described as observed power. The registry record does not report the study’s own sample-size justification. Any planning illustration based on an observed effect should be understood as an illustrative calculation rather than the study’s original design rationale. This distinction is especially important for this study because it is listed as single group, whereas a two-arm equal-allocation assumption would not describe its registered design. No numerical sample-size result is reported in the registry record.

What statistical analysis details are absent?

The record lists 0 analyses. It does not report an analysis plan, a method for estimating MTD, a method for handling missing observations, an interim-analysis approach, multiplicity adjustment, or defined analysis populations. In general, these details determine how observations are converted into estimates and how uncertainty is characterized. Their absence means readers cannot determine from the registry record whether a particular estimate was prespecified, how deviations were handled, or how many participants contributed to each outcome. The record also does not report a dose-response model or a formal comparison across dose levels.

The registry summary mentions a biomarker rationale involving MGMT promoter hypermethylation or low expression. In general, a predictive biomarker analysis asks whether treatment effects differ according to biomarker status, and requires both biomarker measurement and an appropriate analysis. No MGMT outcome or analysis is reported in the registry record. The rationale should not be read as evidence that a biomarker association was demonstrated in this study.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures and identifies maximum tolerated dose as the primary outcome, with pathological complete response among the secondary outcomes. It does not report a full list of outcome definitions and analyses, an analysis plan, or any adjustment for multiple testing. The registry record therefore does not establish whether a multiplicity strategy was prespecified or how multiple outcomes were handled. This matters because interpretation can differ when several outcomes are examined, particularly if results are selected for emphasis after analysis.

Missing-data methods are not reported in the registry record. The record does not state how participants who did not complete treatment, lacked an assessment, or had an unevaluable outcome were handled. It also does not identify analysis populations for the primary and secondary outcomes. Enrollment is listed as 22, but that does not establish the denominator used for each outcome.

The number of analyses listed is 0. This does not show that no analyses were performed; it means the registry record does not list analysis results. No interim-analysis plan, stopping rule, dose-escalation decision method, or statistical analysis plan is reported. These omissions limit assessment of prespecification, outcome selection, and the handling of incomplete information. They also prevent a detailed appraisal of whether reported safety counts and endpoint definitions were applied consistently across participants.

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 non-serious adverse event terms

The registry lists serious adverse events as affecting 0 of 2 participants at Dose Level 1, 0 of 2 at Dose Level 2, and 0 of 18 at Dose Level 3/Recommended Dose. For “other” adverse events, the listed affected counts are 2 of 2, 2 of 2, and 18 of 18, respectively. These are descriptive counts within the registry’s safety groups. The record does not list named serious event terms, and the detailed types and severity of “other” events are not reported in the registry record.

A zero serious-event count means none was recorded in the listed at-risk group; it is not evidence that the underlying risk is zero. The small size of some groups also limits how precisely their event experience can be characterized. The “other” counts should not be interpreted as showing that all participants experienced the same event or the same level of harm. The registry does not report deaths, so death outcomes are not reported in the registry record.

Because there is no randomized comparator, these counts cannot establish that one dose level caused more or fewer events than another. They also cannot by themselves identify the MTD, which depends on the defined dose-limiting toxicity endpoint and dose-finding procedure.

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

This record describes a phase I study of preoperative chemoradiation with capecitabine and temozolomide for locally advanced resectable rectal cancer. It documents a single-group design, enrollment listed as 22, a primary outcome of maximum tolerated dose, and safety counts across three dose-level groups. These details show the study’s early-phase dose-finding focus and provide a limited account of the reported safety categories.

The record does not report the MTD result, the dose amounts tested, or the criteria used to define dose-limiting toxicity. It therefore does not establish the selected dose or how precisely it was estimated. Although pathological complete response is listed as a secondary outcome, the result is not reported. The registry also does not report a comparative efficacy analysis, a control group, or biomarker findings. The study’s rationale about MGMT should not be mistaken for evidence of a biomarker effect.

The safety entries show no serious adverse events listed among the at-risk participants in the three dose groups, while the “other” category lists all participants in those groups as affected. These counts need cautious interpretation because specific event descriptions, complete adverse-event definitions, and uncertainty estimates are not reported. They do not establish the absence of risk or demonstrate comparative differences between doses.

More generally, a completed study record is not equivalent to a complete statistical report. Without outcome estimates, analysis methods, confidence intervals, and information about missing data and analysis populations, the posted record cannot support a detailed assessment of effect size, precision, or robustness. It describes what the study set out to examine and some recorded safety counts, but leaves the principal dose-finding result unavailable.

13. Why This Trial Matters Statistically

This study illustrates a central distinction in clinical biostatistics: a trial’s design and endpoint can be clear even when the registry does not report the outcome needed to answer its main question. Here, the primary endpoint is an MTD definition tied to dose-limiting toxicity, but the registry does not state the resulting dose. Recognizing that gap prevents a design description from being mistaken for a study finding.

It also highlights why dose-level groups should not automatically be read as comparative arms. The study is registered as single group, with allocation marked not applicable and no masking. The dose groups are part of a dose-finding assessment and are not identified as randomized control and intervention groups. Treating them as a controlled comparison would misstate the design and invite causal conclusions the record does not support.

The safety entries offer another useful statistical lesson. Counts describe observed events in groups of particular sizes; they do not, by themselves, establish the underlying event probability or the difference in risk between groups. In general, uncertainty is important when interpreting small-group estimates, especially zero counts. The absence of confidence intervals and detailed event definitions in the registry limits precision and clinical interpretation.

Finally, the registry’s biomarker rationale and secondary outcome listing demonstrate the difference between a research motivation and a reported result. MGMT is discussed as a rationale, and pathological complete response is listed as an outcome, but neither is accompanied by findings in the record. Keeping these distinctions explicit supports accurate, appropriately limited interpretation of early-phase clinical research.

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 primary limitation for interpretation is that the registry does not report the primary MTD result. It also omits the temozolomide dose amounts, complete dosing details, dose-limiting toxicity criteria, and the decision process used to select the recommended dose. Without these, the central dose-finding conclusion cannot be independently evaluated from the registry record.

The study is listed as single group with no masking, and no randomized comparator is described. The dose-level safety groups should not be treated as like-for-like comparison arms. The registry’s safety information is limited to affected and at-risk counts; detailed event terms, severity information for the “other” category, and death results are not reported in the registry record. The listed zero serious-event counts therefore do not establish an absence of risk.

Outcome reporting is also incomplete. Pathological complete response is listed as a secondary outcome, but its result is not reported. The record lists six outcome measures and 0 analyses, without a complete analysis plan or analysis-population definitions. Missing-data handling, interim analyses, multiplicity procedures, and confidence intervals are not reported. Enrollment of 22 does not establish the number evaluated for each outcome.

The study summary mentions MGMT as part of the scientific rationale, but biomarker measurement and findings are not reported in the registry record. The registry also does not report the study’s sample-size justification. These limitations restrict assessment of precision, outcome completeness, prespecification, and the relevance of the biomarker rationale to observed results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Preoperative CRT With Temozolomide Plus Capecitabine in Rectal Cancer — NCT01781403.
• Registry record last updated 2021-02-04; status last verified 2021-01.
• Results first posted 2016-06-23.
• 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

NCT01781403 is a completed phase I, single-group study sponsored by Asan Medical Center. The registry lists enrollment as 22 and describes preoperative chemoradiation with capecitabine, temozolomide, and radiotherapy for locally advanced resectable rectal cancer. Masking is listed as none, and allocation is not applicable.

The primary outcome is maximum tolerated dose in mg/m^2, assessed over 5-6 weeks during study treatment. Pathological complete response is listed as a secondary outcome. The registry lists three dose-level safety groups, with at-risk counts of 2, 2, and 18. Serious adverse events are listed as affecting 0 participants in each group; “other” adverse events are listed for all participants at risk. The primary and secondary outcome results, detailed event descriptions, and analysis methods are not reported in the registry record.