Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) for Recurrent Glioblastoma Multiforme (GBM): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) for Recurrent Glioblastoma Multiforme (GBM) (NCT01067469), a randomized phase 2 study. The primary outcome is Progression Free Survival (PFS).

2. Clinical Question

The registry describes this as a phase II trial intended to study whether the combination could help control glioblastoma and to study its safety. The statistical question is narrower than a claim about treatment benefit: what progression-free survival values were recorded, how uncertain are those estimates, and what can be concluded from the available comparisons? The trial’s randomized allocation gives the comparison a planned experimental structure, but the numerical results must still be read in light of the reported endpoint analyses and their limits.

3. Trial Design

The registry identifies this as a randomized phase II trial with no masking. M.D. Anderson Cancer Center is listed as the sponsor. The recorded enrollment is 83. The registry lists a start of 2010-01, primary completion of 2016-10, and status as completed. Randomization procedures, allocation concealment, stratification factors, and any blinding of outcome assessment are not reported in the registry record.

The two treatment groups were standard-dose bevacizumab and low-dose bevacizumab plus lomustine. The posted primary endpoint results include 36 participants for standard-dose bevacizumab and 33 for the combination. These endpoint denominators are not the same as the overall enrollment figure. The registry record does not explain the relationship between enrollment and the numbers contributing to these endpoint results, so the difference should not be attributed to a particular reason.

The primary outcome was median progression-free survival, measured from registration until documented progression or death from any cause, whichever came first, and assessed up to 1 year. The description specifies that progression was assessed with MRI and that the time origin was trial registration, not randomization into chemotherapy arms after surgery for recurrent tumor. The listed secondary outcomes include radiographic response, 6-month progression-free survival, overall survival, time to progression, and treatment-related toxicities. Results are posted for only some of these outcomes. The registry record does not report the full protocol, a sample-size justification, the randomization method, or a detailed statistical analysis plan.

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: Of the 83 participants enrolled 12 were screen failures and therefore never assigned to treatment arms.

Overall Study

Reasons for not completing this period:

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 Progression Free Survival (PFS), measured over Documented from the date of registration until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 1 year.

Progression-free survival (PFS) is the time from the defined starting point until the first of documented disease progression or death from any cause. In this trial, the starting point was registration, rather than randomization into chemotherapy arms after surgery for recurrent tumor. Progression was assessed using MRI scans, and the outcome was assessed up to 1 year.

The registry reports median PFS for each group. A median describes the time by which half of the relevant participants have experienced the event, under the analysis used. It is a time-to-event summary: participants who have not yet progressed or died by the end of their observed follow-up may contribute information up to that point without being treated as though the event occurred then. The registry record does not provide enough detail to establish the precise censoring rules or analysis population.

PFS is used in clinical trials because it captures the time until disease progression or death, rather than only whether an event occurred at a single fixed visit. The posted medians are accompanied by 95% confidence intervals, which express uncertainty around each estimate. They do not, by themselves, provide a formal statistical test of the difference between groups. No between-group PFS comparison or hazard ratio is reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The posted results use different statistical summaries for different types of outcomes. PFS is a time-to-event endpoint and is reported as a median with a 95% confidence interval for each treatment group. The 6-month PFS outcome is reported as a percentage of participants, with a confidence interval, and has an additional unadjusted comparison. Treatment-related toxicities are recorded as participant counts. These summaries answer different questions and should not be interpreted as if they were interchangeable.

What does a median PFS estimate describe?

For a time-to-event outcome, the median is a single summary of the event-time distribution: the time by which half of the participants are estimated to have experienced progression or death. It does not describe every participant’s experience, and it does not state how many months an individual participant will remain progression-free. Participants may have different follow-up durations. A time-to-event analysis can account for participants whose event has not been observed by the end of their follow-up, but the censoring rules and detailed analysis method are not reported in the registry record.

The registry defines PFS from registration until documented progression or death from any cause, whichever came first, with assessment up to 1 year. It also states that PFS was determined from registration, not from randomization into chemotherapy arms after surgery for recurrent tumor. These definitions matter because changing the starting point or event definition changes the quantity being summarized. The registry record does not provide further detail about how MRI assessments were scheduled, how ambiguous progression was handled, or how missing assessments affected the analysis.

How should the confidence intervals be read?

A confidence interval conveys uncertainty in an estimate under the statistical method used. The reported 95% confidence intervals for median PFS are 2.96 to 5.55 months for standard-dose bevacizumab and 2.96 to 8.34 months for low-dose bevacizumab plus lomustine. The point estimates are the reported medians; the intervals show that each estimate is uncertain, with the combination-group interval spanning a broader range. A confidence interval is not a guarantee that the true value lies within its limits, and it does not directly provide the probability that one treatment is better than another.

Each group’s confidence interval is an estimate about that group. A direct treatment comparison requires an analysis of the contrast between groups, with its own estimate and uncertainty. The registry record does not report such a primary PFS comparison. Therefore, the medians and their separate intervals are descriptive evidence, not a substitute for a reported comparative analysis.

What does the 6-month PFS comparison add?

The 6-month PFS result treats status at a fixed time as a binary outcome: participants are counted according to whether they are progression-free at 6 Months. The posted group estimates are percentages with 95% confidence intervals. The unadjusted risk difference for low-dose bevacizumab plus lomustine relative to standard-dose bevacizumab is 0.141, with a 95% confidence interval from -0.072 to 0.354 and p = 0.196. The confidence interval includes zero, while the unadjusted p-value does not indicate a statistically clear difference by conventional interpretation. This result is an additional endpoint analysis, not the missing formal comparison of median PFS.

A p-value measures how unusual data at least as discrepant as those observed would be under a specified null hypothesis and the assumptions of the test. It is not the probability that the null hypothesis is true, nor a measure of clinical importance. The comparison is described as unadjusted; the registry record does not report adjustment for other variables or for multiple endpoint testing.

Why does over-dispersion matter generally?

As a general statistical point, over-dispersion occurs when count variation is greater than a model assumes. If a count model assumes less variation than the data contain, uncertainty can be understated and tests can appear more decisive than warranted. The posted primary outcome is a time-to-event summary, and the secondary outcomes are proportions or participant counts. The registry record does not report a count model or an over-dispersion assessment, so no conclusion about either can be drawn for this trial.

What do the planning illustrations mean?

The posted sample-size illustrations use two-sided significance level 0.05, equal allocation, and a normal approximation. They show participants per arm for 80% power and participants per arm for 90% power when planning for 100%, 75%, or 50% of the observed 6-month PFS effect. The corresponding values are 162 and 216 for planning for 100% of the observed effect; 278 and 371 for planning for 75% of the observed effect; and 600 and 802 for planning for 50% of the observed effect.

These are planning illustrations calculated from the observed effect, not the design justification for this trial. They do not represent the power achieved by the completed study, and they should not be interpreted as observed power. The registry record does not report the trial’s own sample-size assumptions or justification. The illustrations also concern the fixed-time binary outcome, not the primary median PFS endpoint.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes in addition to the primary PFS endpoint. When several outcomes or comparisons are examined, the chance of at least one apparently unusual result can increase. Statistical procedures can control this multiplicity, for example by adjusting tests or by defining a prespecified sequence of hypotheses. The registry record does not report whether such a procedure was planned or used, and it does not identify a testing hierarchy. The unadjusted secondary comparison should therefore not be treated as if it had been protected against multiple testing.

Some listed secondary outcomes have no results or analyses reported in the registry record. The record does not state whether those outcomes were not collected, not analyzed, or simply not posted. It also does not report how missing outcome data were handled, what analysis populations were used, or whether analyses followed an intention-to-treat principle. These omissions prevent a full appraisal of whether the posted results include all randomized participants for each outcome and how participants with incomplete follow-up contributed.

The primary endpoint description specifies MRI-based assessment and follow-up up to 1 year, but the registry record does not report the frequency of assessments, censoring rules, or a detailed missing-data strategy. These choices can matter for time-to-event estimates, especially when follow-up is incomplete or event ascertainment differs. No imputation method, sensitivity analysis, or treatment of protocol deviations is reported in the registry record.

The posted endpoint denominators are smaller than the total enrollment figure, but the registry record does not explain why. It would be inappropriate to infer whether this reflects exclusions, missing observations, withdrawals, or another reason. Without participant disposition and analysis-population details, the extent and potential impact of missing data cannot be determined. These limitations affect the strength of inference from both the primary estimates and the secondary comparisons.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: confusion (5.7%), muscle weakness - generalized (5.7%), cns ischemia (5.6%), fracture (5.6%), cns hemorrhage (2.9%).

The adverse-event summary records serious adverse events in 9 of 36 participants at risk in the standard-dose bevacizumab group and 9 of 35 participants at risk in the low-dose bevacizumab plus lomustine group. Other adverse events are recorded in 26 of 36 and 23 of 35 participants, respectively. The recorded death counts are 6 and 1. These are descriptive counts and do not establish that an event or death was caused by treatment. The registry record does not report the causes of death or their relationship to treatment.

Serious adverse-event counts refer to participants with serious events, not necessarily to the total number of event episodes. A participant can experience more than one event, and the posted participant count does not convey event timing, duration, severity beyond the serious classification, or recurrence. The registry also lists serious-event terms with percentages, including confusion and generalized muscle weakness at 5.7%, CNS ischemia and fracture at 5.6%, and CNS hemorrhage and cholecystitis at 2.9%. The record does not clearly assign these listed percentages to a treatment group in the summary, so they should not be used to compare groups.

Differences in these descriptive counts are not a substitute for a prespecified safety comparison. Definitions, exposure duration, follow-up completeness, and attribution details are not reported in the registry record. The figures describe the safety information posted, not a causal estimate of treatment-related risk.

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

The primary results show that the reported median PFS estimates were 4.11 months for standard-dose bevacizumab and 4.34 months for low-dose bevacizumab plus lomustine, with the confidence intervals stated in the endpoint results. They also show that the estimates have uncertainty and that the registry does not report a formal between-group analysis for this primary time-to-event outcome. The record therefore supports a description of the posted group estimates, not a firm conclusion that one regimen produced longer or shorter PFS.

The 6-month PFS comparison supplies an unadjusted estimate and interval, but the interval includes zero. The posted result does not establish a difference between groups. The other secondary outcomes and safety counts add descriptive context, but their interpretation is limited by absent analyses, absent multiplicity details, and missing information about analysis populations and missing data. The record does not report enough information to assess the robustness of the results across alternative analytic choices.

These results do not establish equivalence. A failure to demonstrate a difference is not proof that two treatments have the same effect. Equivalence or non-inferiority requires an appropriate design, a prespecified margin, and an analysis suited to that question; such information is not reported in the registry record. Nor do the posted results establish that either treatment is effective or ineffective. They describe measured outcomes in this trial and the precision with which some of those outcomes were estimated.

The findings should be understood in the context of a completed randomized phase II study with recorded enrollment of 83 and outcome-specific denominators of 36 and 33 for the primary PFS results. The registry record does not provide a full account of participant flow, the detailed analysis plan, or all listed secondary results. Those limitations restrict conclusions about the treatment contrast and the generalizability of the posted estimates. The statistical interpretation is therefore cautious: the record supplies group summaries and selected secondary findings, but not a reported primary comparative estimate sufficient to settle the comparative question.

13. Why This Trial Matters Statistically

This trial illustrates why a randomized label and a pair of group-specific medians do not by themselves answer a comparative statistical question. The primary endpoint is time-to-event, but the registry record reports median PFS and confidence intervals for each group without a formal between-group comparison. Readers can describe each estimate and its uncertainty, but cannot reconstruct a sponsor-reported treatment contrast from those summaries alone.

It also demonstrates that endpoint denominators and overall enrollment are distinct pieces of information. The registry records enrollment of 83, while the primary outcome results list 36 and 33 participants by group. Without participant-flow details, the reasons for the endpoint denominators are unknown. That gap matters because transparent analysis populations help readers judge who contributed to each estimate and whether missing outcomes could affect interpretation.

The 6-month PFS analysis offers a different statistical view: a fixed-time proportion and an unadjusted risk difference. It is informative as a descriptive secondary result, but it is not a substitute for the primary time-to-event comparison and should be weighed in light of multiple listed outcomes and absent multiplicity details. The posted planning illustrations also provide a useful distinction between retrospective planning scenarios and a trial’s original design. They are not evidence of observed power, and they do not reveal the sample-size justification used for the trial.

Together, these features make the record useful for statistical reading: it shows the importance of endpoint definitions, uncertainty, comparative analyses, and reporting completeness. It also shows why a cautious interpretation can be more informative than treating a point estimate or unadjusted result as a definitive conclusion.

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.

Several limitations specific to this trial affect interpretation of the posted results. Most importantly, the primary endpoint is presented as group-specific median PFS with confidence intervals, but a formal comparison between the randomized groups is not reported in the registry record. The central comparative question therefore cannot be answered from a sponsor-reported primary analysis in the registry. The record also does not report a hazard ratio or the statistical model used for a comparative time-to-event analysis.

The primary PFS definition sets registration as the time origin, while the description notes that registration preceded randomization into chemotherapy arms after surgery for recurrent tumor. The record does not explain how this timing relates to individual treatment exposure or provide further detail on the interval between registration and treatment allocation. It does not report the MRI assessment schedule, censoring rules, or handling of incomplete scans. These details are relevant to understanding how progression times were determined.

The recorded enrollment is 83, while the posted primary PFS denominators are 36 and 33. Participant disposition and reasons for these endpoint denominators are not reported in the registry record. The record does not specify whether all randomized participants were analyzed in their assigned groups, nor does it describe missing-data methods or sensitivity analyses.

Several secondary outcomes are listed without results or analyses in the registry record. The record does not describe a multiplicity plan, endpoint hierarchy, full statistical analysis plan, or sample-size justification. Safety summaries include participant counts, but detailed event definitions, exposure time, attribution, and causes of death are not reported. These reporting gaps do not invalidate the posted estimates, but they limit how confidently their precision, completeness, and comparative meaning can be assessed.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Standard Dose Bevacizumab Versus Low Dose Bevacizumab Plus Lomustine (CCNU) for Recurrent Glioblastoma Multiforme (GBM) — NCT01067469.
• Registry record last updated 2020-03-17; status last verified 2020-03.
• Results first posted 2020-03-17.
• 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

The registry record describes NCT01067469 as a completed randomized phase II trial sponsored by M.D. Anderson Cancer Center. It compared standard-dose bevacizumab with low-dose bevacizumab plus lomustine in adults with recurrent glioblastoma multiforme. The recorded enrollment is 83; the registry lists a start of 2010-01 and primary completion of 2016-10.

The primary outcome was median progression-free survival, defined from registration to documented progression or death from any cause and assessed up to 1 year. The posted medians were 4.11 months for standard-dose bevacizumab and 4.34 months for the combination, with 95% confidence intervals. A formal between-group primary analysis is not reported in the registry record. Selected secondary outcomes and safety counts are also posted, while results for other listed outcomes, participant-flow details, and a full statistical analysis plan are not reported in the registry record.