Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer (NCT02340949), a randomized phase 2 study. The primary outcome is Number of Patients Achieving Pathologic Complete Response (pCR)..

2. Clinical Question

The central statistical contrast is between the two named treatment strategies, not between aflibercept and no treatment in isolation: both groups are described as receiving induction chemotherapy followed by chemoradiation and surgery. Random allocation is recorded, but the allocation procedure and any stratification factors are not reported in the registry record.

3. Trial Design

The registry describes NCT02340949 as a Phase II, randomized, multicenter, open-label, parallel-group trial. Its title identifies induction FOLFOX with or without aflibercept followed by chemoradiation in high risk locally advanced rectal cancer. The record lists enrollment as 180 and status as completed. The listed start is 2015-01, and primary completion is dated 2019-07-15.

The treatment groups are mFOLFOX6 + Aflibercept and mFOLFOX6. The intended sequence in the summary is induction treatment, standard chemoradiation, and surgery. The chemoradiation is described as capecitabine combined with 50.4 Gy in 28 days. The listed drug interventions include aflibercept, 5-fluorouracil, oxaliplatin, and leucovorin. The registry arm descriptions give mFOLFOX6 dosing details, although the descriptions available in the record are incomplete.

Open-label means that masking is recorded as none; the registry therefore does not describe treatment assignment as concealed from participants or investigators after allocation. Randomization can help balance prognostic factors across groups on average, while open-label conduct can affect care, outcome ascertainment, or reporting. Pathologic response is assessed in tissue, but the record does not report whether pathologists were masked to treatment assignment.

The record names Grupo Espanol Multidisciplinario del Cancer Digestivo as sponsor. It reports no analysis records. The registry does not report the randomization method, allocation ratio, site count, protocol deviations, adherence, participant flow, or the reasons for any withdrawals. These details would help assess how the planned randomized comparison was carried out and which participants contributed to each outcome.

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

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 Number of Patients Achieving Pathologic Complete Response (pCR)., measured over From baseline until 2 years and 2 months.

The primary endpoint is the number of participants achieving pathologic complete response (pCR). The registry defines pCR as the absence of viable tumor cells in both the primary tumor and lymph nodes, denoted T0N0. The stated timeframe runs from baseline until 2 years and 2 months. The endpoint is a count of participants, so it represents a binary outcome at the participant level: a participant either meets the stated pCR definition or does not.

Pathologic response is used in this trial because the definition is based on examination of tumor and lymph-node tissue after the treatment sequence. A clearly specified pathological definition helps make the outcome interpretable across treatment groups. It is distinct from an imaging response: the registry lists MRI changes as a secondary outcome and defines those changes in terms of T downstaging.

For a treatment comparison, the count alone is not enough to show the size or precision of a group difference. Interpretation would ordinarily require the pCR result for each group and an effect estimate with uncertainty, along with a clear account of the analysis population and outcome assessment. A single comparative result for the primary endpoint is not reported in the registry record. The registry also indicates that the primary outcome has several categories or time points and was not reduced to one comparison. Thus the endpoint definition can be described, but the primary treatment contrast cannot be quantified from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Clinical trial results combine a design, an outcome definition, an analysis, and an estimate of uncertainty. The registry record supplies some design and endpoint information for NCT02340949, but it does not report analysis records or a single comparative result for the primary outcome. The following concepts explain how such a comparison is ordinarily read without attributing unreported methods to this trial.

What does randomization contribute?

Randomization assigns participants to treatment groups using a chance process. In general, this can reduce systematic differences in prognostic characteristics between groups at the point of assignment. It does not guarantee that groups will be identical, and it cannot by itself prevent bias after allocation. The registry identifies the trial as randomized but does not report the sequence-generation method, concealment procedures, allocation ratio, or stratification factors. It is therefore possible to describe the randomized design, but not to assess those operational details.

The record describes a parallel-group comparison of mFOLFOX6 with aflibercept versus mFOLFOX6 without aflibercept. In a parallel design, each participant is assigned to a group and followed under that assigned strategy, rather than switching through treatments as part of a crossover design. The registry records no masking. In general, lack of masking can influence treatment delivery, additional care, subjective assessments, or reporting. The record does not say whether outcome assessors were masked for pathology review.

How should a binary endpoint be analyzed?

The primary endpoint counts participants who achieve pCR, defined as no viable tumor cells in the primary tumor and lymph nodes (T0N0). This is a binary participant-level outcome. A comparative analysis would ordinarily report the number meeting the definition in each group, the relevant denominators, an effect estimate, and an uncertainty measure. Effect estimates for binary outcomes may be expressed in different ways, such as a difference in event probabilities or a ratio of probabilities. These express different scales and should not be conflated. The registry does not report a single comparative pCR analysis or its estimate.

General statistical reasoning treats the denominator as essential. A count without the number of participants assessed cannot show how common the outcome was in a group. The analysis population also matters: an intention-to-treat analysis generally retains participants in their randomized groups, while other analysis populations may exclude participants for specified reasons. The registry record does not report which population was used for the primary endpoint or how missing pathology assessments were handled.

What does uncertainty add?

A point estimate describes the observed comparison under a chosen scale; a confidence interval conveys its statistical uncertainty. A narrower interval generally indicates greater precision under the model assumptions, while a wider interval indicates less precision. A confidence interval is not a guarantee about the true effect, and its interpretation depends on the design and analysis. No primary-outcome point estimate or confidence interval is reported in the registry record, so precision cannot be assessed for the pCR comparison.

A p-value is another summary tied to a statistical model and a null hypothesis. It is not a measure of the probability that a treatment works, nor does it describe the magnitude of an effect. A small p-value does not substitute for an effect estimate and its uncertainty. No primary-outcome p-value is reported in the registry record. It is therefore not appropriate to characterize the pCR comparison as statistically significant or not statistically significant.

What do the planning assumptions mean?

The registry’s sample-size assumptions describe planning illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation. The illustrated target effect is expressed as a stated fraction of the observed effect. For time-to-event outcomes, the stated approach gives a total number of events using the Schoenfeld method; for other outcomes, it gives participants per arm. These are planning assumptions, not a report of the trial’s original design rationale. The record does not report the trial’s own sample-size justification.

General sample-size calculations estimate the amount of information needed under specified assumptions about an effect, variability or event frequency, significance level, power, and allocation. A calculation based on an observed effect is an illustration and can be especially sensitive to how that observed effect was estimated. It does not measure the power actually achieved in the completed trial. The registry record does not provide numeric planning results in the information available for this analysis, nor does it report the assumptions underlying the original trial design.

Over-dispersion is a general concern when observed variability exceeds what a statistical model assumes. If present and not handled appropriately, it can make uncertainty estimates too small. This trial’s primary endpoint is a binary count, and the registry record does not report a model or any over-dispersion assessment. It would be inappropriate to claim that over-dispersion was present or that a particular model was used.

Why do outcome timing and multiplicity matter?

The primary outcome timeframe is from baseline until 2 years and 2 months, while the secondary outcome list includes disease-free survival at 3 years. Outcomes measured over different periods answer different questions and can have different analysis requirements. The registry notes that the primary outcome has several categories or time points and was not reduced to one comparison. It does not report which time point or category was intended to control the primary inference, or how repeated measurements were handled.

When a study tests multiple outcomes, time points, or comparisons, the chance of obtaining at least one apparently notable result can increase if multiplicity is not addressed. General approaches include defining a primary comparison in advance, adjusting significance thresholds, or treating secondary analyses as exploratory. The registry record does not report a multiplicity strategy, so none should be assumed.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome and several secondary outcomes, including pathological efficacy measures, MRI changes, adverse events, surgical complications, and disease-free survival at 3 years. It also notes that the primary outcome has several categories or time points and was not reduced to one comparison. The record does not report a prespecified strategy for choosing among those categories or time points, nor does it report whether multiplicity adjustments were planned or applied.

In general, examining multiple outcomes or time points creates multiple opportunities to observe results that appear notable by chance. A prespecified hierarchy or adjustment can help control the interpretation of multiple tests. Without a reported strategy, the results of any unadjusted analyses would need to be interpreted with caution. No comparative primary analysis is reported in the registry record, so the effect of any multiplicity approach on the primary conclusion cannot be assessed.

Missing-data handling is also not reported. For the pCR endpoint, the record does not state how participants without evaluable pathology, missing assessments, or incomplete follow-up were handled. It does not report whether missing values were excluded, imputed, or addressed through sensitivity analyses. Those choices can affect the analysis denominator and the interpretation of a binary outcome.

The registry reports no analysis records. It does not identify an intention-to-treat, per-protocol, or safety population for the primary endpoint, and it does not describe protocol deviations or exclusions. The available information therefore does not establish which participants contributed to each efficacy analysis. These gaps limit reproducibility and prevent readers from checking whether the reported population aligns with the randomized groups.

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: hypertension (29.6%), neutropenia (21.7%), diarrhoea (7.0%), mucosal inflamation (3.5%), thrombocytopenia (3.1%).

The serious adverse-event records list mFOLFOX6 + Aflibercept with 115 participants at risk and 45 affected, and mFOLFOX6 with 65 at risk and 16 affected. These are the recorded serious-event counts and denominators; the registry information does not explain their relationship to the enrollment field or to the efficacy analysis population. They should not be treated as a direct comparison of risk without the event definition, observation period, and analysis method.

The listed serious adverse-event terms and percentages are Hypertension, 29.6%; Neutropenia, 21.7%; Diarrhoea, 7.0%; Mucosal inflamation, 3.5%; Thrombocytopenia, 3.1%; and Palmar-plantar erythrodysesthesia syndrome, 2.6%. The registry record does not specify the denominator or calculation basis for these percentages in the information available for this analysis. They should therefore be read as registry-listed percentages, not assumed to be percentages of participants in a particular treatment group.

The safety fields also record deaths as 12 for mFOLFOX6 + Aflibercept and 7 for mFOLFOX6. The registry information does not report cause, timing, or attribution to treatment. A recorded death count alone does not establish whether deaths were treatment-related. Safety interpretation requires the definitions and follow-up context for each event as well as an appropriate comparison of the groups.

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

This trial addresses a defined comparative question: whether induction mFOLFOX6 with aflibercept, followed by chemoradiation and surgery, differs from the same sequence without aflibercept in pathologic complete response. The registry identifies the population as high risk locally advanced rectal cancer selected by MRI and defines pCR as T0N0, with no viable tumor cells in the primary tumor or lymph nodes. Those details clarify the scope of the question.

The registry record does not report a single comparative pCR result. It therefore does not establish the observed difference between groups, the precision of that difference, or whether a statistical test crossed a prespecified threshold. No numerical conclusion about the primary treatment contrast can be drawn from the endpoint definition, the enrollment field, or the safety counts.

Even when a treatment-group difference is reported, statistical interpretation and clinical interpretation are separate. An estimate can be uncertain, and an estimate with statistical evidence of a difference does not by itself establish how important that difference is in clinical practice. Conversely, an imprecise estimate does not show that the groups are equivalent. The registry information does not include the pCR estimate or its uncertainty needed for that assessment.

The trial design also has boundaries. It is a Phase II, randomized, open-label study, and the registry does not report masking of outcome assessors, the analysis population, missing-data methods, or a multiplicity plan. These omissions do not negate the randomized design, but they limit assessment of the analysis and the robustness of any conclusion. The listed secondary outcomes do not substitute for reported results.

The record supports a description of what was planned and how the primary outcome was defined. It does not support a claim that either induction strategy produced a better response, nor a conclusion about the balance of benefits and harms. Those judgments require outcome results and their statistical context, which are not reported in the registry record.

13. Why This Trial Matters Statistically

The trial is statistically interesting because it frames a randomized comparison around adding aflibercept to an induction chemotherapy regimen, while holding the subsequent treatment sequence as described in the registry summary. This design focuses the clinical question on the incremental contribution of aflibercept within the planned sequence, rather than comparing entirely different treatment pathways.

The primary endpoint is pathologic complete response, a binary outcome with a stated pathological definition. That clarity helps readers understand what event is counted. At the same time, the registry’s note that the primary outcome has several categories or time points and was not reduced to one comparison illustrates why a clear endpoint definition is not sufficient: the analysis must also specify the comparison and timing that support the primary inference.

The trial record also illustrates the value of separating efficacy interpretation from safety interpretation. Serious adverse-event counts, listed event terms, and death counts describe safety information, but their meaning depends on denominators, follow-up, event definitions, and attribution. The record does not provide enough context to turn those entries into a complete comparative safety assessment.

More broadly, this study highlights how registry completeness affects statistical interpretation. Randomization, phase, masking, treatment groups, outcome definitions, and dates are recorded. Yet analysis records, a comparative pCR estimate, uncertainty measures, missing-data handling, analysis populations, and multiplicity methods are not reported in the information available for this analysis. Without those elements, readers can understand the intended question but cannot assess the primary result’s magnitude or precision.

Its statistical importance therefore lies in both the design question and the limits of the recorded results: a randomized comparison can be identified, while the main efficacy contrast remains unquantified in the registry record.

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 important trial-specific limitation for interpreting efficacy is the absence of a single comparative result for the primary pCR outcome. The registry defines the endpoint and its timeframe, but does not report group-specific pCR counts, an effect estimate, a confidence interval, or a p-value. It also notes that the primary outcome has several categories or time points and was not reduced to one comparison.

The registry identifies the trial as open-label and reports masking as none. It does not state whether pathology assessors were masked to treatment assignment. Because the primary outcome is based on pathological assessment, information about assessment procedures would help readers judge whether knowledge of treatment could have influenced classification. That information is not reported in the registry record.

The record does not report the randomization method, allocation concealment, analysis populations, participant flow, protocol deviations, adherence, or missing-data procedures. It is consequently not possible to determine from the record whether the analyzed participants were retained in their randomized groups or how incomplete outcome assessment was addressed. The enrollment field and the safety denominators are presented without an explanation of their relationship.

The listed secondary outcomes broaden the questions the trial intended to examine, but their results are not reported in the information available for this analysis. A multiplicity strategy is also not reported. These omissions make it difficult to assess how secondary findings, if available elsewhere, relate to the primary question.

The safety entries require caution because the record does not specify the denominator basis for the listed serious-event percentages, the observation period, or the cause and treatment attribution of deaths. These limitations are specific to interpreting the registry entries and do not justify assumptions about what the underlying trial found.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Induction FOLFOX With or Without Aflibercept Followed by Chemoradiation in High Risk Locally Advanced Rectal Cancer — NCT02340949.
• Registry record last updated 2021-05-03; status last verified 2021-04.
• Results first posted 2021-05-03.
• 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

NCT02340949 is a completed, randomized, parallel-group, open-label Phase II trial sponsored by Grupo Espanol Multidisciplinario del Cancer Digestivo. Its title concerns induction FOLFOX with or without aflibercept followed by chemoradiation in high risk locally advanced rectal cancer. Enrollment is listed as 180; the record gives a start of 2015-01 and primary completion on 2019-07-15.

The comparison is mFOLFOX6 + Aflibercept versus mFOLFOX6. The primary outcome is the number of participants achieving pCR, defined as no viable tumor cells in the primary tumor and lymph nodes (T0N0), from baseline until 2 years and 2 months. The summary describes subsequent chemoradiation and surgery.

The registry lists secondary pathological, MRI, safety, surgical, and disease-free survival outcomes. It reports no analysis records and does not provide a single comparative primary-outcome result. The record therefore identifies the trial question and endpoint but does not permit a numerical interpretation of the primary treatment contrast.