Bevacizumab in Combination With Metronomic Temozolomide for Recurrent Malignant Glioma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bevacizumab in Combination With Metronomic Temozolomide for Recurrent Malignant Glioma (NCT00501891), a na phase 2 study. The primary outcome is 6-Month Progression-free Survival.

2. Clinical Question

In practical terms, the study sought to describe the 6-month progression-free survival outcome for participants receiving the combination, alongside response and safety outcomes. Because it was a single-group phase II study, its primary endpoint describes outcomes among participants in this treatment group; it cannot by itself establish how those outcomes compare with what would have occurred under another treatment or without the study combination. The record lists response rate, hemorrhage, and selected toxicity outcomes as secondary outcomes. It does not provide an analysis entry for those outcomes.

3. Trial Design

This was a completed phase II study sponsored by Duke University. The registry lists a single-group design, with allocation marked as not applicable and masking listed as none. Enrollment was 32. The listed condition is glioblastoma multiforme, while the study title and description refer more broadly to recurrent malignant glioma.

Participants were assigned to a single treatment group receiving bevacizumab and metronomic temozolomide. The record describes up to 12 cycles, each lasting 28 days. Bevacizumab was described at 10 mg/kg every other week, beginning a minimum of 7 days after a biopsy or 28 days after a craniotomy. The temozolomide dose text ends at “50” in the registry record, so its full dose description is not reported there.

The primary outcome was 6-month progression-free survival, expressed as a percentage of participants. The registry defines progression-free survival from the start of study treatment until documented progression according to the Macdonald criteria, or death from any cause. The record identifies the primary endpoint population as intent to treat.

The study began in 2007-07, and primary completion is listed as 2007-12. Its status is completed. The record lists response rate and adverse-event outcomes as secondary outcomes, including CNS or systemic hemorrhage and specified severe toxicity categories. It does not report a randomized comparator, a masking procedure, or a parallel control arm. Therefore, the study design supports description of outcomes in the treated group, not a randomized comparison of treatment strategies.

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

Analysis population for the primary outcome, as defined in the registry: Intent to treat

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 6-Month Progression-free Survival, measured over 6 months.

The primary endpoint is the percentage of participants surviving 6 months from the start of study treatment without disease progression. The registry defines progression-free survival as the time from treatment initiation to the first documented progression according to the Macdonald criteria, or death due to any cause. This endpoint combines progression and death as events, so a participant who experiences either does not meet the definition of being progression-free at the 6-month time point.

In general, progression-free survival is used to describe how long participants remain alive without documented worsening of disease. It can be useful in studies where both tumor status and survival matter, and it gives a time-specific summary when reported as a percentage at a defined follow-up point. Interpretation depends on how progression is assessed and whether follow-up is complete and consistently conducted. The registry describes MRI assessment, neurological performance, and concomitant steroid use as components of the adapted Macdonald evaluation.

The endpoint is reported as a percentage with a 95% confidence interval. A confidence interval conveys statistical uncertainty around an estimated percentage; it does not show the range of outcomes for individual participants. The registry record does not report the observed percentage or confidence interval, so the endpoint’s estimated level and precision cannot be evaluated from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the endpoint estimate?

The endpoint is a proportion: the percentage of participants meeting the registry’s definition of alive and progression-free at 6 months. The event definition counts documented progression or death from any cause as a failure to remain progression-free. This is a fixed-time summary of a time-to-event outcome. It is not the same as an average duration of progression-free survival, and it does not describe how long each individual participant remained free of progression.

In general, a proportion is interpreted together with its denominator and the rules used to classify participants. The registry identifies the primary population as intent to treat, but does not report the number with known 6-month status or explain how participants without sufficient follow-up were handled. Therefore, the endpoint’s denominator and missing-data handling cannot be independently assessed from the record.

What does a confidence interval convey?

The registry specifies a 95% confidence interval for the primary percentage, but does not report its value. In general, a confidence interval describes uncertainty in an estimate arising from sampling variability under the statistical method used. A narrower interval indicates greater precision under that method; a wider interval indicates less precision. It does not mean that individual participant outcomes fall within the interval, and it does not account for every possible source of bias or uncertainty.

Because neither the estimate nor the interval is reported, readers cannot judge the primary result’s precision or assess which values are compatible with the posted data. The stated confidence level alone is not a substitute for the interval limits.

Why does the single-group design matter?

In general, a single-group study estimates outcomes observed in the enrolled group, but it does not directly estimate a treatment contrast against a concurrent control. Without random allocation to a comparator, differences from an external benchmark may reflect differences in eligibility, disease severity, supportive care, outcome assessment, or follow-up, as well as any treatment effect. The registry lists no randomized comparison and no control arm. Consequently, the design is suited to describing the group’s outcomes, not establishing a comparative causal effect.

How should the sample-size illustration be read?

The registry-related planning illustration is described as using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It is based on a fraction of an observed effect. These assumptions describe a hypothetical planning calculation, not the design of this single-group trial. The illustration is not observed power and is not evidence that the study had a particular probability of detecting an effect. The registry record does not report the trial’s own sample-size justification or design assumptions. Any planning counts should be read as hypothetical participant requirements under their stated assumptions, not as outcomes observed in this study.

What is not available about the analysis?

The registry lists 4 outcome measures and no analysis entries. It does not report a statistical analysis plan, a model for estimating the primary percentage, adjustment variables, interim analyses, or a multiplicity procedure. The absence of analysis entries does not establish that no analyses were conducted; it means the analysis details are not reported in the registry record.

In general, analysis choices matter because they determine how outcome information is summarized, how uncertainty is quantified, and how incomplete observations are treated. For a percentage endpoint, the approach to participants whose 6-month status is unknown can affect both the estimate and its precision. For a study with multiple outcomes, multiplicity methods may matter when several statistical tests are used to support formal conclusions. No specific method in those areas can be attributed to this study from the posted record.

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("Bevacizumab and Metronomic Temozolomide")
n      <- c(32)
events <- c(6)
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  Bevacizumab and Metronomic Temozolomide  32  6  18.8  7.2  36.4  8.9  35.3  9.0  35.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 4 outcome measures: the primary 6-month progression-free survival endpoint and secondary outcomes covering response rate, hemorrhage, and selected toxicity categories. It reports no analysis entries. A formal multiplicity strategy, such as how statistical evidence across multiple outcomes would be interpreted or adjusted, is not reported in the registry record. The listed outcomes alone do not show whether any tests were conducted or how their results were interpreted.

The primary endpoint population is labeled intent to treat. That label identifies the stated analysis population, but the record does not explain which enrolled participants had evaluable follow-up, whether all participants were included in the reported estimate, or how missing endpoint status was handled. The observed primary percentage and its confidence interval are also not reported. As a result, readers cannot assess the effect of missing follow-up on the primary estimate.

In general, missing outcome data can affect an estimate when the participants whose outcomes are unknown differ systematically from those with observed outcomes. The direction and size of any such effect depend on why observations are missing and on the analysis method. Neither the reasons for missingness nor a missing-data method is reported.

The record does not report a statistical analysis plan, an interim-analysis approach, or a sample-size justification for the trial. Those omissions should be treated as unavailable information, not as evidence that a particular method was or was not used.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death nos (9.4%), colitis (3.1%), diarrhea (3.1%), hemorrhoids (3.1%), pancreatitis (3.1%).

The registry lists 8 participants with serious adverse events among 32 at risk, and 15 participants with other adverse events among 32 at risk. These are group-level counts from the posted safety information. They describe the number of participants recorded with events; they do not establish that the events were caused by the study drugs.

The serious-event term listing includes Death NOS at 9.4%, followed by colitis, diarrhea, hemorrhoids, pancreatitis, and lung infection at 3.1% each. The term percentages describe the entries as reported; they should not be treated as a full account of all possible safety outcomes or as estimates of comparative risk. The adverse-event summary does not report a death count, so Death NOS as a listed serious event term should not be read as a reported count of deaths.

The registry also names hemorrhage and selected severe toxicity categories as secondary outcomes, but the posted record does not provide their outcome results in the analysis entries. Safety interpretation is therefore limited to the posted counts and event terms. Without a concurrent comparison group, these data do not provide a randomized estimate of excess risk or comparative safety.

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

The study record establishes that a completed phase II, single-group study evaluated bevacizumab with metronomic temozolomide in recurrent malignant glioma. It defines 6-month progression-free survival as the primary endpoint, describes the event definition, identifies the primary population as intent to treat, and posts selected adverse-event information.

It does not report the primary endpoint percentage or its 95% confidence interval. Thus, the posted record does not permit a statistical assessment of how frequently participants were alive without progression at the specified follow-up point, or how precise that estimate was. It also does not provide analysis entries for the listed secondary outcomes. The registry’s completion status does not substitute for reported endpoint results.

Even if the primary percentage were available, the single-group design would not support a direct randomized comparison with another treatment or control. A proportion observed in this group would describe its outcomes, but would not isolate the effect of the combination from other influences on outcomes. Comparisons with outside studies would require careful consideration of differences in participants, care, outcome definitions, and follow-up.

The posted safety counts and terms are descriptive. They can indicate which events were recorded in the group, but do not establish causation or comparative risk. The registry does not report a death count in the adverse-event summary, nor does it provide results for the listed hemorrhage and selected toxicity outcomes.

Accordingly, the record supports a description of the study design and its intended endpoint, but not a conclusion about the primary outcome’s magnitude or precision, or a comparative conclusion about efficacy or safety.

14. Why This Trial Matters Statistically

This trial illustrates why study design and outcome reporting must be considered together. The primary endpoint is a clinically interpretable fixed-time summary: the percentage alive without progression at 6 months. Yet the registry record does not report the estimate or its confidence interval. Without those values, readers cannot assess either the observed outcome or its statistical precision.

The single-group structure is also central to interpretation. A group-level outcome can be informative as a description, but it does not provide the direct treatment contrast created by a randomized control group. This distinction is important when readers encounter a percentage or event count: an observed outcome is not, by itself, evidence of what would have happened under an alternative strategy.

The record also shows why registry status and outcome availability are separate issues. The study is listed as completed, and enrollment and endpoint definitions are described, but the primary outcome is not reported in the record. Likewise, the presence of named secondary outcomes does not mean their analyses or results are available.

Finally, safety figures need context. Counts and event terms convey what was recorded in the treatment group, but without a comparator and detailed attribution information they cannot quantify comparative risk. Statistically, the most defensible reading is therefore bounded: use the registry’s design and definitions to understand the study question, and distinguish those details from results that are not reported.

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 most important limitation of the available record is that it does not report the primary endpoint result. The 6-month progression-free survival percentage and its 95% confidence interval are not reported in the registry record, preventing assessment of the estimate and its precision. Analysis entries for the listed outcomes are also absent.

The study was single-group, with no randomized comparator. This prevents a direct within-trial comparison and limits causal interpretation of any group outcome. The registry also lists no masking. As a result, outcome assessment and reporting cannot be assumed to have been blinded; the record does not describe additional procedures to reduce assessment bias.

The endpoint definition refers to the Macdonald criteria and describes MRI findings, neurological performance, and steroid use as components of assessment. However, details of assessment frequency, assessor agreement, adjudication, and follow-up completeness are not reported in the registry record. The number of participants with known endpoint status and the handling of missing follow-up are also not reported.

The study’s treatment description is incomplete for temozolomide: the dose text ends at “50”. Although bevacizumab dosing and cycle structure are described, the incomplete dose detail limits the regimen description. The registry names secondary response and safety outcomes but does not report analyses for them. The serious-event summary supplies selected counts and terms, but does not report a death count or establish event attribution.

Finally, the record does not report the trial’s statistical analysis plan, sample-size justification, interim analyses, or multiplicity approach. These absences limit evaluation of how the study was planned and how its outcomes were analyzed.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Bevacizumab in Combination With Metronomic Temozolomide for Recurrent Malignant Glioma — NCT00501891.
• Registry record last updated 2013-05-27; status last verified 2013-03.
• Results first posted 2013-04-22.
• 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

This completed phase II study evaluated bevacizumab with metronomic temozolomide in recurrent malignant glioma. The registry lists glioblastoma multiforme as the condition, a single-group design, and enrollment of 32. Bevacizumab was described at 10 mg/kg every other week, with up to 12 cycles of the combination and 28 days per cycle. The temozolomide dose description is incomplete.

The primary endpoint was the percentage of participants alive without progression at 6 months, with progression or death counted as an event. The primary population is labeled intent to treat. The registry record does not report the primary percentage or its 95% confidence interval, and it lists no analysis entries.

Posted safety information lists 8 participants with serious adverse events and 15 with other adverse events among 32 at risk. The study has no randomized comparator, so its design does not support a like-for-like control comparison. The record does not report the statistical analysis plan, missing-data handling, multiplicity approach, or trial sample-size justification.