Combination Chemotherapy, Bev, RT, and Erlotinib in Treating Patients With Stage III Non-Small Cell Lung Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combination Chemotherapy, Bev, RT, and Erlotinib in Treating Patients With Stage III Non-Small Cell Lung Cancer (NCT00280150), a non-randomized phase 1, phase 2 study. The primary outcome is Maximum Dose of Erlotinib When Given Together With Carboplatin, Paclitaxel, and Thoracic Conformal Radiotherapy (Phase I [Closed to Accrual as of 1/3/2008]).

2. Clinical Question

The broader study purpose included examining side effects and the best dose of bevacizumab and erlotinib when given with combination chemotherapy and radiation therapy, as well as assessing how the regimen performed in this patient group. The primary endpoint is narrower: it concerns dose-limiting toxicities during the phase I objective, not a randomized estimate of benefit relative to another treatment.

The registry also lists secondary outcomes concerning progression-free survival, response to induction therapy, overall response and survival, and feasibility and tolerability of consolidation therapy. These give context for the study’s scope, but the registry record does not report analyses for those outcomes. The clinical question can therefore be described from the planned objectives and treatment groups, but the posted information does not establish an observed dose-limiting-toxicity result or comparative treatment effect.

3. Trial Design

This was a completed phase I/II trial sponsored by UNC Lineberger Comprehensive Cancer Center. The registry lists an enrollment of 46 and describes the study as nonrandomized, unmasked and single-group. Those design features matter: the listed cohorts do not constitute a randomized comparison, and the record does not provide a like-for-like control group for estimating the effect of the regimen against another treatment.

The interventions included bevacizumab, carboplatin, paclitaxel, erlotinib hydrochloride and three-dimensional conformal radiation therapy. The registry describes a bevacizumab plus chemoradiotherapy cohort without erlotinib, cohorts adding erlotinib 100 mg or 150 mg, and a phase II regimen using bevacizumab, erlotinib 100 mg and chemoradiotherapy. It identifies the phase I portion as closed to accrual as of 1/3/2008. The exact participant counts in each cohort are not reported in the registry record.

The listed study start is 2006-01, primary completion is 2012-01, and status is completed. The primary outcome is explicitly a phase I objective; the population description says phase II participants are not included. Thus, the total enrollment should not be read as the size of the phase I population for this endpoint.

The record does not report how participants were assigned among the cohorts, whether cohort entry followed a particular sequence, or how the phase II regimen was selected beyond the endpoint description. A planned enrollment rationale, detailed eligibility criteria, and a full protocol are also not reported in the registry record. Without those details, the design can be summarized as a dose- and regimen-focused early-phase study, but its operational conduct cannot be reconstructed from the posted summary alone.

The intervention descriptions identify treatment components and some doses, but do not provide enough information to infer treatment duration, dose modifications, adherence, or the detailed administration schedule. Those features should not be inferred from the names of the interventions or the study’s phase designation.

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 48 participants screened for eligibility, 46 were deemed eligible and went on to treatment, 1 was ineligible, and 1 was initially ruled eligible but the liver functioning tests (LFTs) continued to increase so the PI felt the participant should not be treated.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: This was a phase I objective only, so the phase II participants are not included.

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 Dose of Erlotinib When Given Together With Carboplatin, Paclitaxel, and Thoracic Conformal Radiotherapy (Phase I [Closed to Accrual as of 1/3/2008]), measured over 6 weeks after completion of therapy.

The primary endpoint is the number of dose-limiting toxicities (DLTs) for the phase I objective. The registry defines a DLT as a grade 3 or 4 nonhematologic toxicity, except that esophagitis had to be grade 4; it also includes grade 4 neutropenia lasting greater than or equal to 7 days and thrombocytopenia to less than 20,000/microliter. The stated timeframe is 6 weeks after completion of therapy.

In general, a DLT endpoint is used in early-phase research to describe treatment toxicity under a specified definition and follow-up window. Here, the registry says DLTs were used to establish which cohort would be used for the phase II portion. The endpoint is a count, rather than a continuous measurement or a time-to-event estimate. The definition determines which toxicities qualify, while the timeframe determines when the endpoint is assessed.

The registry record does not report the observed DLT count, the count by cohort, or which cohort was selected for phase II as a result. It also does not report further details about how DLTs were adjudicated or how participants without complete follow-up were handled. Consequently, the endpoint’s stated purpose and definition can be described, but its observed value and the precision of any dose-selection conclusion cannot be assessed from the posted record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a count endpoint: the number of DLTs during 6 weeks after completion of therapy. It also reports no analyses in the record. The endpoint definition and the analysis method are different things. The definition specifies which events qualify; an analysis method would explain how the resulting counts were summarized or compared. The latter is not reported in the registry record.

What does a count endpoint capture?

In general, a count records how many qualifying events occur in a specified population or observation period. For this study, the registry’s DLT definition determines which toxicities contribute to the count. A count does not, by itself, show how many participants experienced events unless the counting rules specify whether repeat events in one participant are counted separately. That detail is not reported in the registry record. Nor does the record report the observed count or the number of participants assessed.

Because this is a count endpoint, interpretation depends on the population and observation window as well as the event definition. The stated window is 6 weeks after completion of therapy. The registry does not explain how a participant who did not complete therapy or did not have the full follow-up window would be handled. It also does not describe how toxicity grades were assigned or verified. Those omissions limit a detailed appraisal of endpoint ascertainment.

Why is the DLT definition important?

The listed definition includes grade 3 or 4 nonhematologic toxicity, with an exception for esophagitis, which must be grade 4. It also includes grade 4 neutropenia lasting greater than or equal to 7 days and thrombocytopenia to less than 20,000/microliter. In general, a threshold-based definition makes the endpoint operational: events are counted only when they satisfy the stated criteria. A change in the definition could change which events qualify, so the posted definition is central to interpreting any DLT count. The registry does not provide the count needed to apply that interpretation to observed results.

What can be inferred from the study structure?

The trial is described as phase I/II, nonrandomized, unmasked and single-group. In general, random allocation can help balance measured and unmeasured characteristics between comparison groups. Without randomization, cohort comparisons may be influenced by differences between the people who enter each cohort or by other aspects of treatment and follow-up. The record itself cautions that the arms are not a like-for-like control comparison. That means the cohort descriptions should not be read as establishing a causal contrast.

The phase I DLT endpoint was used to establish which cohort would be used for phase II. The registry lists bevacizumab with chemoradiotherapy, versions adding erlotinib 100 mg or 150 mg, and a phase II regimen using erlotinib 100 mg. However, the exact process for moving between cohorts, the allocation procedure, and the decision rule for selecting the phase II cohort are not reported in the registry record. It would be speculative to infer a formal dose-escalation algorithm or a toxicity threshold for selection.

What do estimates and uncertainty usually add?

In general, an estimate summarizes the observed data, while a confidence interval communicates uncertainty around that estimate under the chosen statistical model. A p-value, when used, describes how compatible the observed data are with a specified null model; it is not a measure of clinical importance. For this record, no primary-endpoint estimate, confidence interval or p-value is reported, and the registry lists no analyses. These concepts explain what statistical reporting can contribute, but they cannot fill in the missing trial result.

The endpoint is a count, and the record does not specify a probability model, adjustment method, or other inferential procedure. It does not report whether results were summarized by cohort, whether any covariates were considered, or how uncertainty was calculated. No particular method should be attributed to the investigators on the basis of the endpoint description alone.

How should planning illustrations be read?

The sample-size section contains planning illustrations, not observed trial findings. In general, a sample-size calculation describes how much information a hypothetical design might require under stated assumptions. It does not show that a study actually enrolled that number for an endpoint, and it is not observed power. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect defined as a stated fraction of the observed effect. The record’s comparison is not randomized, and the primary endpoint is a count, so the illustration should not be mistaken for the trial’s documented design rationale or for a formal analysis plan.

The registry does not report the trial’s own sample-size justification. The total enrollment is 46, but that overall figure does not identify the number contributing to the phase I endpoint. Planning figures in the tables and plots should therefore be interpreted separately from actual enrollment and from the unreported primary result.

Finally, the record lists six outcome measures and no analyses. It does not describe an analysis plan for secondary outcomes, treatment of missing data, or adjustment for multiple outcomes. Statistical methods can only be evaluated fully when the endpoint definitions, analysis populations, handling of incomplete observations and the results themselves are available. The registry summary supplies some definitions and design descriptors, but leaves those analytical details unreported.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures and no analyses. Among the secondary outcomes named are progression-free survival, response rate to induction therapy, overall response and survival profile, and feasibility and tolerability of consolidation therapy. The primary outcome is the phase I DLT count. The record does not report whether these outcomes were tested under a prespecified hierarchy, whether any multiplicity adjustment was planned, or how results across outcomes were intended to be interpreted. Those details are not reported in the registry record.

In general, multiplicity arises when several outcomes or comparisons are examined. Without a prespecified strategy, the chance of finding at least one apparently notable result can be difficult to interpret. This is a general statistical concern, not evidence that an unreported adjustment was or was not used in this study. Since no analyses are listed, the posted record does not allow readers to evaluate any multiplicity procedure.

Missing-data methods are also not reported. The registry does not state how incomplete endpoint follow-up, treatment discontinuation, or missing outcome assessments were handled. In general, missing observations can affect both the number of participants contributing to an analysis and the interpretation of its estimates. No assumptions about the reasons for missingness or the method used to address it can be made from the record.

The endpoint population is described as phase I only, with phase II participants excluded. That is the available population distinction for the primary endpoint. The record does not report further analysis-population definitions, such as how participants who began but did not complete treatment were classified. It also does not give the phase I denominator or cohort-specific participant counts. These gaps prevent a fuller assessment of the analysis population and the influence of incomplete data.

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: esophagitis (11.1%), dehydration (4.4%), febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infe (4.4%), infection with unknown anc - esophagus (4.4%), hemorrhage, pulmonary/upper respiratory - bronchus (2.2%).

The overall-study adverse-event summary lists 45 participants at risk for serious adverse events and 19 affected. For the other adverse-event category, it lists 45 at risk and 45 affected. The summary also records 30 deaths. These entries describe what the registry reports for the overall study; they should not be read as proving that the events or deaths were caused by treatment.

The listed serious-event terms include esophagitis at 11.1%, dehydration at 4.4%, febrile neutropenia at 4.4%, infection with unknown ANC - Esophagus at 4.4%, and two hemorrhage or bleeding terms at 2.2% each. The febrile-neutropenia term is visibly truncated in the registry record. These percentages describe the listed terms, but the summary does not provide enough detail to determine whether participants could contribute to more than one term or how events were attributed.

In general, an at-risk count is the denominator for the relevant safety summary, while an affected count describes participants recorded with an event in that category. Serious-event listings do not alone convey timing, duration, recurrence, severity beyond the serious classification, or causal attribution. The record does not report those details. The death count should likewise be read as a descriptive entry, not as a treatment-related death count.

The safety summary is separate from the primary DLT endpoint. A serious adverse event is not necessarily a DLT under the registry’s specific definition, and the record does not provide a mapping between the two. The DLT result remains unreported.

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

This trial record is informative about the question investigators set out to study: whether dose-limiting toxicities could guide selection of a cohort for the phase II portion of a combined treatment regimen in stage III non-small cell lung cancer. It gives the DLT definition, follow-up timeframe, treatment components and cohort descriptions. It also records secondary outcomes of interest and an overall adverse-event summary.

It does not, however, report the observed primary endpoint result. There is no DLT count, cohort-specific result or stated selection conclusion in the registry record. Without those results, readers cannot determine from this record how many qualifying toxicities occurred or how the endpoint informed phase II. The record also does not provide analyses for the listed secondary outcomes.

The trial is nonrandomized and single-group, with no like-for-like control comparison. Consequently, the design cannot establish a treatment effect relative to a randomized control group. Even if outcomes differed among the cohorts, such differences would not automatically be attributable to the treatment components, because cohort allocation was not randomized and the record does not describe the allocation process.

In general, results describe what was observed in a study population; they do not automatically predict what would happen in other settings. Precision depends on the amount and pattern of observed information and the statistical method used. Here, the endpoint estimate and its uncertainty are not reported, so neither the magnitude nor the precision of the primary finding can be assessed.

The posted safety entries are descriptive. They do not establish causation, and the listed deaths cannot be assumed to be treatment-related. The registry also does not report the details needed to assess the relationship between serious adverse events and the DLT definition.

Accordingly, the record supports an account of the study’s design and planned questions, but not a conclusion about the observed DLT outcome, the comparative effect of the regimens, or the certainty of an efficacy result. Missing results should not be interpreted as evidence either for or against a particular outcome.

13. Why This Trial Matters Statistically

This study is statistically notable for the distinction between an early-phase dose-selection question and a comparative treatment-effect question. The primary endpoint is a DLT count intended to help establish which cohort would be used for phase II. That purpose differs from estimating whether one regimen is better than another, especially because the study is nonrandomized and the registry cautions that the arms are not a like-for-like control comparison.

The record also illustrates why endpoint definitions matter. The DLT criteria specify toxicity grades and thresholds, include an exception for esophagitis, and set a follow-up timeframe of 6 weeks after completion of therapy. Such details make an endpoint more interpretable by stating what is counted and when. But a definition alone is not a result: without the observed count and denominator, it cannot show the study’s toxicity findings.

Another statistical lesson is the importance of matching the denominator to the analysis population. Overall enrollment is 46, while the registry says the primary endpoint is for phase I only and excludes phase II participants. The cohort sizes and number assessed for DLT are not reported. Treating overall enrollment as the phase I endpoint denominator would therefore go beyond the posted information.

The planning illustrations should also be kept distinct from the trial’s design and results. In general, planning calculations depend on assumptions and describe hypothetical information needs; they are not observed power and do not replace a documented sample-size rationale. The registry does not report that rationale, and its primary endpoint result is absent.

Finally, the registry lists six outcome measures but no analyses. This makes the distinction between registered questions and reported evidence especially important. The design and endpoint can be described, but readers cannot assess multiplicity handling, missing-data methods, effect estimates or uncertainty from the registry record. Transparent reporting of these elements would be necessary for a fuller statistical interpretation.

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 is that the primary endpoint result is not reported in the registry record. The record names the DLT count, its definition and its timeframe, but does not report the observed count, the number of participants contributing to it, or a cohort-specific summary. The stated purpose was to use DLTs to establish which cohort would be used for phase II, yet the selection result is also absent.

The overall enrollment of 46 does not resolve this limitation because the primary endpoint applies to phase I only and excludes phase II participants. The number in each cohort and the number assessed for the endpoint are not reported. The record also does not describe participant flow or incomplete endpoint follow-up.

The nonrandomized, single-group structure limits interpretation of cohort contrasts. The record explicitly warns that the arms are not a like-for-like control comparison. Allocation procedures, cohort-entry rules and a detailed dose-selection rule are not reported, so the potential for differences between cohorts cannot be assessed from this summary.

Several analytical details are unavailable. No analyses are listed; the registry does not report methods for missing data or multiplicity, an analysis plan, or uncertainty estimates for the primary endpoint. The sample-size justification is not reported. Secondary outcomes are listed, but their definitions and results are not reported.

The safety summary is also limited as a causal account. It records event counts and selected serious-event terms, but does not provide details on timing, recurrence, attribution or the relation between serious events and DLTs. The record lists deaths but does not identify them as treatment-related. These limitations are specific to the information available in this trial record and constrain what can be concluded from it.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Combination Chemotherapy, Bev, RT, and Erlotinib in Treating Patients With Stage III Non-Small Cell Lung Cancer — NCT00280150.
• Registry record last updated 2017-06-19; status last verified 2017-05.
• Results first posted 2017-06-19.
• 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 describes a completed, nonrandomized, unmasked, single-group phase I/II trial sponsored by UNC Lineberger Comprehensive Cancer Center. It lists enrollment of 46, a study start of 2006-01 and primary completion of 2012-01. The study concerned stage III non-small cell lung cancer and combined bevacizumab, chemotherapy and thoracic conformal radiation therapy, with erlotinib included in some cohorts.

The phase I primary endpoint was the number of DLTs within 6 weeks after completion of therapy. The registry says DLTs informed selection of a cohort for phase II and specifies the toxicity criteria. Phase II participants are excluded from the primary endpoint population. The registry record does not report the observed DLT result or the selection conclusion.

The record lists secondary outcomes and an overall adverse-event summary, but no analyses. It does not report a sample-size justification, detailed missing-data methods, multiplicity handling or comparative estimates. The posted information supports a description of the design and registered questions, but not a quantitative conclusion about the primary outcome or a randomized treatment comparison.