Study to Evaluate the Efficacy and Safety of FOLFOX-4 Plus Cetuximab Versus UFOX Plus Cetuximab.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Efficacy and Safety of FOLFOX-4 Plus Cetuximab Versus UFOX Plus Cetuximab. (NCT00439517), a randomized phase 2 study. The primary outcome is Progression-free Survival (PFS).

2. Clinical Question

The comparison concerns two combination regimens, each given with cetuximab, rather than cetuximab versus no cetuximab. The randomized, parallel-group design assigns participants to one of the regimens and evaluates outcomes across those groups. The study is identified as an exploratory phase II trial. Its stated focus is efficacy and safety in first-line treatment of metastatic colorectal cancer.

The registry record lists overall survival, best overall response, several quality-of-life measures, treatment impact, resource use, and safety among secondary outcomes. The numerical results available for best overall response and overall survival offer additional context for the primary progression-free survival result, but they address different outcomes and should not be treated as interchangeable evidence.

3. Trial Design

This was a randomized, open-label, parallel-group phase II study. Participants were assigned to UFOX plus cetuximab or FOLFOX4 plus cetuximab. Masking is recorded as none, so the study was open label. The registry lists enrollment as 302, with 152 participants in the UFOX arm and 150 in the FOLFOX4 arm for the primary endpoint results.

The study population was described as subjects with previously untreated metastatic colorectal cancer. The registry's primary analysis population is the intention-to-treat population, defined there as all randomized subjects. The primary endpoint was progression-free survival. Its timeframe runs from randomization to disease progression, death, or the last tumor assessment, with the recorded reporting period extending from the first patient randomized in February 2007 until the cutoff date of June 30, 2009.

The brief summary describes the study as an exploratory comparison and refers to 400 patients, while the recorded enrollment is 302. The reason for that difference is not reported in the registry record. The original sample-size justification and the trial's original design assumptions are not reported in the registry record.

The registry lists best overall response, overall survival, quality of life measured using FACT-C and EQ-5D, therapy preference, treatment impact on social daily living and health-care resource utilization, and safety as secondary outcomes. The record also lists a planned study duration through the stated cutoff date, but does not describe in detail how follow-up was managed after that date. The primary statistical comparison is reported as a stratified log-rank analysis, with a hazard ratio and confidence interval. Factors used for stratification 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.

Before assignment: A total of 329 participants were screened and 302 participants were included in the Intent to Treat (ITT) Population. One patient included in the ITT population received no study medication and was not included in the Safety Population which comprised 301 participants (151 received UFOX plus cetuximab and 150 FOLFOX4 plus cetuximab).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Intention-to-treat (ITT) population i.e. all randomized subjects .

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 Time from randomization to disease progression, death, or last tumor assessment reported between day of first patient randomised, Feb 2007, until cut off date, 30 Jun 2009.

Progression-free survival measures the time from randomization until disease progression or death due to any cause, according to the endpoint description. The registry specifies that only deaths within 12 weeks of the last tumor assessment are considered events. Participants without an event are censored on the date of their last tumor assessment. Investigators assessed response and progression using RECIST 1.0 criteria.

This endpoint is used to summarize how long participants remain alive without documented progression. It combines progression and death into one time-to-event outcome, so it differs from overall survival, which concerns time to death. The registry reports the median progression-free survival for each randomized group, alongside a 95% confidence interval, and gives a between-group hazard ratio from a stratified log-rank analysis.

In general, time-to-event methods can use information from participants with different lengths of follow-up. Participants who have not had an event by their last assessment contribute information until that point and are then censored. This approach depends on appropriate event and censoring definitions. The posted endpoint description supplies those definitions, but further details about assessment schedules for progression-free survival are not reported in the registry record.

7. Results Posted in the Registry

• UFOX + Cetuximab vs FOLFOX4 + Cetuximab: hazard ratio 0.68 (95% CI 0.52–0.89), reported p = 0.005 (as reported in the registry).

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Best Overall Response (BOR)

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • FOLFOX4 + Cetuximab: 51.3% (77/150) versus 37.5% (57/152) on control; risk difference 13.8 percentage points (95% CI 2.7 to 24.9), risk ratio 1.37 (1.06–1.77); unadjusted two-proportion z-test p = 0.016.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for FOLFOX4 + Cetuximab than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Overall Survival (OS)

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Stratified log rank); it was not recalculated.
• Result:
  • UFOX + Cetuximab vs FOLFOX4 + Cetuximab: hazard ratio 0.85 (95% CI 0.60–1.21), reported p = 0.380 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between UFOX + Cetuximab vs FOLFOX4 + Cetuximab and the control. The interval gives the range of effects that remain compatible with the data.

The secondary results provide a mixed pattern across outcomes and should be interpreted as complementary to, rather than replacements for, the primary progression-free survival analysis. The posted best overall response comparison points in favor of FOLFOX4 plus cetuximab, while the overall-survival estimate is less conclusive: its confidence interval includes 1 and its reported p-value does not indicate clear statistical evidence of a difference. This means the secondary outcomes do not all offer the same degree or type of support for a between-group distinction.

These measures address different aspects of outcome. Response is a categorical assessment of tumor response, overall survival concerns time to death, and progression-free survival includes progression as well as death under the registry’s event definition. Directional similarity across outcomes can be informative, but one outcome cannot be substituted for another. In particular, an estimate favoring one group for response does not establish a corresponding difference in overall survival.

Secondary findings generally carry less weight than a prespecified primary endpoint when many outcomes are examined. Testing multiple outcomes creates more opportunities for apparently notable findings by chance. The registry record does not report a multiplicity adjustment, a hierarchy for secondary outcomes, or a detailed plan for interpreting them. The reported p-values for secondary results should therefore be read as unadjusted evidence for those particular comparisons, not as confirmation across the full set of outcomes.

The record lists quality-of-life measures using FACT-C and EQ-5D, a therapy preference questionnaire, treatment impact on social daily living and health-care resource utilization, and safety among the secondary outcomes. Numerical results for those listed measures are not reported in the registry record. Their absence from the posted numerical results means no conclusion about their comparative findings can be drawn from this record.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Best Overall Response (BOR)
• Overall Survival (OS)
• Overall Survival (OS)
• Quality of Life (QOL) Functional Assessment of Cancer Therapy-Colorectal (FACT-C)
• QOL EuroQuol-5D (EQ-5D) Health Outcome Questionnaire
• QOL Therapy Preference Questionnaire (TPQ)
• Treatment Impact on Social Daily Living and Health Care Resource Utilization
• Safety - Number of Patients Experiencing Any Adverse Event

9. Statistical Interpretation

10. Statistical Methods Explained

The primary endpoint is time-to-event data: each participant has a time from randomization to the defined event or, if no event is recorded, to censoring at the last tumor assessment. The registry reports the median for each group and uses a stratified log-rank analysis for the comparison. The factors used to create strata are not reported in the registry record.

What does a median time-to-event result describe?

In general, a median is the point in an outcome distribution at which half the observations are on either side. For a time-to-event outcome, the median is estimated while accounting for participants whose follow-up ends before an event is recorded. It is not an average follow-up time, and it does not describe the event time for every participant. The registry reports median progression-free survival of 6.6 months for UFOX plus cetuximab and 8.2 months for FOLFOX4 plus cetuximab.

How should the hazard ratio be read?

In general, a hazard ratio compares the event rates between groups over follow-up, as represented by the analysis model. A value of 1 corresponds to equal estimated hazards; a value below 1 indicates a lower estimated hazard in the numerator group relative to the denominator group, and a value above 1 indicates a higher estimated hazard. The reported primary comparison is ordered as UFOX plus cetuximab versus FOLFOX4 plus cetuximab. Its hazard ratio is 0.677. A hazard ratio does not directly express a difference in median survival time, nor does it by itself show the absolute probability of an event at a particular time.

What does the stratified log-rank test do?

In general, the log-rank test compares the event experience of groups across observed event times. A stratified version carries out that comparison within specified strata and combines information across them. This can account for prespecified grouping factors in the analysis, but the registry record does not name the factors used in this trial. The method is appropriate for time-to-event comparisons, but its interpretation depends on the endpoint definition, follow-up, censoring, and the analysis assumptions. Details beyond the posted definition and reported method are not reported in the registry record.

What do the confidence interval and p-value contribute?

A confidence interval gives a range of estimates compatible with the observed data under the statistical method and its assumptions. The primary hazard-ratio interval is 0.515 to 0.889 at the 95% confidence level. The reported p-value is 0.005. In general, a p-value describes how incompatible the observed data are with a specified null hypothesis, assuming that hypothesis and the analysis assumptions hold. It is not the probability that the null hypothesis is true, and it does not measure the size or practical importance of an effect. The interval adds information about estimate precision and the range of relative effects compatible with the analysis.

How does the response analysis differ?

Best overall response is a binary outcome expressed as the percentage of participants with the specified response. The registry reports an analysis using the Cochran-Mantel-Haenszel method and an odds ratio. In general, an odds ratio compares the odds of an outcome between groups; it is not the same quantity as a difference in percentages or a risk ratio. The registry also gives a recalculated unadjusted risk difference, which is a separate summary based on the posted group counts and percentages. The sponsor-reported odds ratio and the unadjusted risk-difference calculation use different measures and should not be read as conflicting estimates of the same parameter.

The registry reports overall survival as a median time-to-event outcome and gives a stratified log-rank hazard ratio. The same general distinction applies: medians summarize the group distributions, while a hazard ratio compares event rates over follow-up. The overall-survival estimate is not a substitute for the progression-free survival result, because death is the event of interest for overall survival, whereas progression-free survival includes disease progression as well.

The primary population is the intention-to-treat population, described as all randomized subjects. In general, an intention-to-treat analysis retains participants in their randomized groups, preserving the basis of the randomized comparison. The record does not provide further details on missing observations, treatment changes, or analysis populations for each secondary outcome. Beyond the censoring rule stated for progression-free survival, these matters are not reported in the registry record.

11. Confidence Intervals and Precision

The primary median estimates are 6.6 months for UFOX plus cetuximab, with a 95% confidence interval from 5.6 to 7.2 months, and 8.2 months for FOLFOX4 plus cetuximab, with a 95% confidence interval from 7.5 to 9.2 months. These intervals describe uncertainty around each group’s median estimate. They should not be interpreted as ranges containing most individual participants’ progression-free survival times.

For the between-group analysis, the reported hazard ratio is 0.677, and its 95% confidence interval extends from 0.515 to 0.889. The interval excludes 1, which is consistent with the reported p-value of 0.005 for the stratified log-rank analysis. The confidence interval still allows a range of relative hazard estimates, so the point estimate should not be treated as exact. Precision also depends on the amount of event and follow-up information; the registry does not give a detailed account of those data beyond the posted results.

The overall-survival hazard ratio is 0.855, with a 95% confidence interval from 0.603 to 1.213. That interval includes 1, indicating that the data are compatible with a range of relative hazards that includes no difference. The corresponding reported p-value is 0.380. This is less precise evidence for a between-group difference than the primary progression-free survival result, and it should not be converted into a claim of equivalence.

Confidence intervals are statistical summaries, not guarantees about the true value or about future participants. They also do not account for unreported design or analysis details. The trial’s original sample-size justification and the factors used in stratification are not reported in the registry record.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effect, not a report of the trial’s original design calculations. For the time-to-event outcomes, the figures are total events needed across the study. For the other outcome, they are participants per arm. The assumptions listed for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect; the time-to-event calculations use the Schoenfeld method.

The 80% power column describes the event total or per-arm enrollment that would give the stated design a probability of 80% of detecting the specified effect if that effect and the assumptions used for the illustration were true. The 90% power column gives the corresponding planning quantity for a probability of 90%. These are design probabilities, not probabilities that a result is true. Smaller effects are harder to detect and require more events or participants under the stated assumptions, which is why the planning figures rise as the assumed fraction of the observed effect becomes smaller.

The displayed planning rows use the full observed effect, 75% of the observed effect, and 50% of the observed effect. Their required totals or per-arm counts differ by outcome because the effect estimates and outcome types differ. This is not observed power.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

d is the total number of events needed (Schoenfeld's formula) with 1:1 allocation and proportional hazards.

Worked calculation for this trial

1. Hazard ratio HR = 0.677, so ln(HR) = -0.3901.
2. d = 4 × (1.96 + 0.842)² / [ln(0.677)]² = 206.3, rounded up to 207 events in total for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
hr <- 0.677                              # observed hazard ratio
events_needed <- function(power, frac = 1) ceiling(round(4 * (z_a + qnorm(power))^2 / log(hr^frac)^2, 6))   # Schoenfeld, 1:1 allocation
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: events = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(events_needed(0.80, f), big.mark = ","), format(events_needed(0.90, f), big.mark = ",")))

# Simulation: given d total events under proportional hazards, events in the treatment arm are Binomial(d, hr / (1 + hr)).
# The score (log-rank type) statistic is (D1 - d / 2) / sqrt(d / 4).
set.seed(439517)
d    <- events_needed(0.80)
reps <- 20000
D1 <- rbinom(reps, d, hr / (1 + hr))
z  <- (D1 - d / 2) / sqrt(d / 4)
cat(sprintf("Simulated power with %s events: %.3f (%d replicates)\n", format(d, big.mark = ","), mean(abs(z) > z_a), reps))

Output from running the code

100% of observed effect: events = 207 (80% power), 277 (90% power)
 75% of observed effect: events = 367 (80% power), 492 (90% power)
 50% of observed effect: events = 826 (80% power), 1,105 (90% power)
Simulated power with 207 events: 0.802 (20000 replicates)

The simulation uses the fact that, with d events in total and proportional hazards, the number of events in the treatment arm is binomial. It is an approximation that conditions on the total number of events, and it should land close to the target power.

14. Group-Sequential Design Analysis

Many time-to-event trials, especially in oncology, stop or report early when interim data are overwhelming, so a single fixed-sample number understates the real design problem. The calculation below is an illustrative group-sequential design built from this trial's posted control median and hazard ratio. The registry record does not state the planned number of looks or the spending function, so the design is a planning illustration, not a reconstruction of the protocol. Assumed: one-sided α = 0.025, 90% power, three equally spaced looks on information, Lan-DeMets O'Brien-Fleming spending, 24 months of accrual, 60 months in total and a 1% monthly dropout hazard.

Under these assumptions the design needs about 316 participants in total, with the boundaries below.

Fixed design versus group-sequential alternatives

Group-sequential designs cost a small increase in maximum sample size and events compared with the fixed design, in exchange for the chance to stop early for overwhelming efficacy. O'Brien-Fleming spending keeps early boundaries very conservative and the final boundary close to the fixed-design value, whereas Pocock spending spends more alpha early.

Sensitivity to a smaller true effect

Planning for exactly the observed effect is optimistic, because observed effects in published trials tend to be somewhat larger than the true effect. The table repeats the main design (three looks, O'Brien-Fleming spending, 90% power) for smaller true hazard ratios.

For context, this trial enrolled 302 participants.

Cross-check, upper boundaries: gsDesign 3.71, 2.511, 1.993 | rpact 3.71, 2.511, 1.993. Agreement between the two packages confirms the boundary calculation.

R code and output

suppressWarnings(suppressMessages({ library(gsDesign); library(rpact) }))
med_control <- 6.6          # control-arm median, months (converted from the posted unit)
hr          <- 0.677          # hazard ratio used for planning
lambdaC     <- log(2) / med_control
eta         <- 0.01               # dropout hazard per month (assumption)
acc_months  <- 24                 # accrual duration (assumption)
study_months<- 60                 # total study duration (assumption)

design <- function(k, sfu, beta, h = hr) gsSurv(k = k, test.type = 1, alpha = 0.025, beta = beta, sfu = sfu,
  lambdaC = lambdaC, hr = h, hr0 = 1, eta = eta, gamma = 1, R = acc_months, T = study_months, minfup = study_months - acc_months)

# Main design: 3 looks, Lan-DeMets O'Brien-Fleming spending, one-sided alpha 0.025, 90% power
x <- design(3, sfLDOF, 0.10)
cat(sprintf("N_TOTAL|%s\n", format(ceiling(sum(x$gamma * x$R)), big.mark = ",")))
for (i in 1:3) cat(sprintf("GS|%d|%.1f|%.0f|%.3f|%.5f|%.5f\n", i, x$T[i], x$n.I[i], x$upper$bound[i], pnorm(-x$upper$bound[i]), cumsum(x$upper$spend)[i]))
cat("\n"); print(gsBoundSummary(x))

# Comparison of designs
cmp <- list(list("Fixed design, one analysis", 1, sfLDOF), list("Two looks, O'Brien-Fleming", 2, sfLDOF),
            list("Three looks, O'Brien-Fleming", 3, sfLDOF), list("Three looks, Pocock", 3, sfLDPocock))
cat("\n")
for (b in c(0.20, 0.10)) for (d in cmp) {
  y <- design(d[[2]], d[[3]], b)
  cat(sprintf("DES|%s|%d|%.0f|%s|%.1f\n", d[[1]], round(100 * (1 - b)), tail(y$n.I, 1), format(ceiling(sum(y$gamma * y$R)), big.mark = ","), tail(y$T, 1)))
}

# Sensitivity: what if the true effect is smaller than the observed one? (3 looks, O'Brien-Fleming, 90% power)
cat("\n")
for (fr in c(1, 0.75, 0.5)) {
  y <- design(3, sfLDOF, 0.10, exp(log(hr) * fr))
  cat(sprintf("SENS|%.2f|%.3f|%.0f|%s\n", fr, exp(log(hr) * fr), tail(y$n.I, 1), format(ceiling(sum(y$gamma * y$R)), big.mark = ",")))
}

# Independent cross-check of the boundaries with rpact
r <- getDesignGroupSequential(kMax = 3, alpha = 0.025, beta = 0.10, sided = 1, typeOfDesign = "asOF", informationRates = x$timing)
cat(sprintf("\nCross-check, upper boundaries: gsDesign %s | rpact %s\n", paste(round(x$upper$bound, 3), collapse = ", "), paste(round(r$criticalValues, 3), collapse = ", ")))

Method: LachinFoulkes 
    Analysis               Value Efficacy
   IA 1: 33%                   Z   3.7103
      N: 212         p (1-sided)   0.0001
  Events: 93        ~HR at bound   0.4629
   Month: 16    P(Cross) if HR=1   0.0001
             P(Cross) if HR=0.68   0.0338
   IA 2: 67%                   Z   2.5114
      N: 316         p (1-sided)   0.0060
 Events: 186        ~HR at bound   0.6917
   Month: 25    P(Cross) if HR=1   0.0060
             P(Cross) if HR=0.68   0.5603
       Final                   Z   1.9930
      N: 316         p (1-sided)   0.0231
 Events: 279        ~HR at bound   0.7875
   Month: 60    P(Cross) if HR=1   0.0250
             P(Cross) if HR=0.68   0.9000



Cross-check, upper boundaries: gsDesign 3.71, 2.511, 1.993 | rpact 3.71, 2.511, 1.993

15. Analyses Reported by the Sponsor

The primary result is the sponsor-reported stratified log-rank hazard ratio of 0.677, with a 95% confidence interval of 0.515 to 0.889 and p = 0.005. The posted analysis does not flag a discrepancy for this comparison, so the sponsor’s analysis is the result to use when describing the primary finding. The same applies to the reported overall-survival hazard ratio of 0.855, with its 95% confidence interval and p-value.

For best overall response, the sponsor reports an odds ratio of 1.756 using the Cochran-Mantel-Haenszel method. The recalculated unadjusted comparison instead expresses the result as a risk difference. Because these are different effect measures and the methods differ, their numerical estimates are not expected to match. The record does not flag a discrepancy requiring the sponsor’s analysis to take precedence over a recalculation.

Recalculations from posted summary statistics are simple, unadjusted analyses and may not reproduce an analysis that accounts for stratification or other model features. They are useful for checking the broad interpretation and showing an alternative effect scale, but they do not replace the sponsor’s reported method when the registry presents one.

16. Multiplicity, Missing Data and Analysis Populations

The registry reports several secondary outcomes in addition to the primary progression-free survival endpoint. When multiple outcomes are analyzed, the chance of at least one apparently notable result can increase. Statistical methods can address this through prespecified hierarchies or adjustment procedures, but a multiplicity strategy is not reported in the registry record. It is also not reported whether interim analyses were planned or conducted, or whether any such analyses affected the testing strategy.

The record identifies the primary analysis population as intention-to-treat, meaning all randomized subjects. This helps define which participants contribute to the primary comparison and preserves the randomized group assignment for that analysis. Further information about missing data, treatment discontinuations, protocol deviations, or handling of missing secondary-outcome measurements is not reported in the registry record.

For progression-free survival, the registry describes censoring participants without an event at their last tumor assessment. It also specifies that only deaths within 12 weeks of the last tumor assessment count as events. These rules define how observed follow-up contributes to the endpoint. Additional detail about the extent of censoring, reasons for missing assessments, and sensitivity analyses is not reported in the registry record.

The primary method is a stratified log-rank test, but the stratification factors are not identified. A detailed statistical analysis plan, including the original sample-size justification and any prespecified subgroup analyses, is not reported in the registry record. These omissions do not change the posted estimates, but they limit assessment of how closely the reported analyses follow an original prespecified plan. The record’s exploratory-study description is relevant context when weighing the primary and secondary findings.

17. 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: diarrhoea (8.6%), vomiting (6.0%), pyrexia (5.3%), central line infection (3.3%), abdominal pain (3.3%).

The posted safety results report serious adverse events for 151 participants at risk in the UFOX plus cetuximab group, with 52 experiencing a serious adverse event. In the FOLFOX4 plus cetuximab group, 150 participants were at risk and 48 experienced a serious adverse event. The registry also reports any adverse event for 151 of 151 participants at risk in the UFOX group and 146 of 150 at risk in the FOLFOX4 group. These counts describe the posted safety populations, which are not identical in size to the primary endpoint groups.

The serious-event terms listed include diarrhoea at 8.6%, vomiting at 6.0%, pyrexia at 5.3%, central line infection at 3.3%, abdominal pain at 3.3%, and ileus at 3.3%. These are event-term percentages, not a complete description of severity, duration, recurrence, or causal attribution. The record does not provide the number of deaths in either safety group. Safety figures should be read as descriptive event counts and reported terms; they do not, on their own, establish a comparative safety profile.

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

The primary result shows a difference in the reported progression-free survival analysis between the randomized groups. The sponsor-reported hazard ratio for UFOX plus cetuximab versus FOLFOX4 plus cetuximab is 0.677, with a 95% confidence interval of 0.515 to 0.889 and p = 0.005. The reported medians are 6.6 months and 8.2 months, respectively. These statistics describe the study’s observed data under its endpoint definition and analysis method.

The result does not show that every participant in one group experienced a longer progression-free period than every participant in the other group. A hazard ratio is a group-level time-to-event comparison, and medians summarize distributions rather than individual outcomes. The estimates also do not establish what would happen in a different population or under different follow-up conditions.

The registry’s secondary findings are not uniform in their strength. The response comparison points in one direction, while the overall-survival comparison has an interval that includes 1 and a reported p-value of 0.380. Secondary outcomes listed without numerical results cannot be interpreted from the registry record. Since multiplicity handling is not reported, the secondary analyses should be treated cautiously.

The study is identified as exploratory and phase II. The reported results are evidence about the randomized comparison in this trial, not a standalone basis for broad conclusions beyond it. The record does not report the original design assumptions, detailed missing-data procedures, or a multiplicity plan. Those limits affect how completely the evidence can be evaluated, but they do not erase the posted primary estimate or its stated uncertainty.

19. Why This Trial Matters Statistically

This trial illustrates why time-to-event studies commonly report more than a single median. The medians describe the observed progression-free survival distributions, while the hazard ratio summarizes a relative comparison over follow-up. The confidence interval conveys uncertainty around that relative estimate. Reading these measures together avoids treating the median values as if they were the complete comparison.

It also demonstrates the importance of comparison order. The reported primary hazard ratio is explicitly for UFOX plus cetuximab versus FOLFOX4 plus cetuximab. Interpreting the estimate without checking that order could reverse the verbal description of its direction. The endpoint definition matters as well: progression-free survival includes progression and death under specified rules, whereas overall survival concerns death.

The additional outcomes show why evidence across endpoints requires care. Response, progression-free survival, overall survival, quality of life, and safety measure different domains. Their findings need not have the same apparent strength, and unadjusted secondary tests do not carry the same evidential role as a primary analysis. The registry’s exploratory designation and missing multiplicity details are therefore important context.

Finally, the distinction between the recorded enrollment and the brief summary’s reference to 400 patients highlights the value of checking what a registry record says about enrollment and analysis populations. The record lists 302 enrolled and reports primary arm counts of 152 and 150. Clarifying the reason for the difference between the summary description and recorded enrollment would require information not reported in the registry record.

20. 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 record identifies the study as exploratory, and it does not report the original sample-size justification or original design assumptions. As a result, the reported enrollment cannot be assessed against a stated planned target using the registry record alone. The brief summary refers to 400 patients, whereas the recorded enrollment is 302; the reason for that difference is not reported in the registry record.

The study was open label, with masking recorded as none. The primary endpoint includes investigator-assessed progression using RECIST 1.0 criteria. The registry does not provide information about whether outcome assessments were independently reviewed or whether any procedures were used to limit assessment bias. Such details are not reported in the registry record.

The primary comparison uses a stratified log-rank method, but the stratification factors are not stated. The registry also does not report the analysis plan for multiple endpoints, interim analyses, or detailed missing-data procedures. For progression-free survival, censoring and event definitions are described, but information on the extent and reasons for censoring is not reported.

Numerical results are available for the primary endpoint and selected secondary outcomes, but not for all listed secondary measures. The listed quality-of-life, preference, treatment-impact, and resource-use outcomes therefore cannot be evaluated from the posted results. Safety data include serious and any adverse-event counts and selected serious-event terms, but the number of deaths in the safety groups is not reported. These record-specific gaps limit a complete assessment of outcome coverage and analysis choices.

21. Related Tutorials

22. Related Statistical Calculators

23. Sources

• ClinicalTrials.gov: Study to Evaluate the Efficacy and Safety of FOLFOX-4 Plus Cetuximab Versus UFOX Plus Cetuximab. — NCT00439517.
• Registry record last updated 2014-06-27; status last verified 2014-06.
• Results first posted 2011-06-14.
• 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.

24. Record Summary

The registry describes a randomized, open-label, parallel-group phase II study of UFOX plus cetuximab versus FOLFOX4 plus cetuximab as first-line therapy for previously untreated metastatic colorectal cancer. Recorded enrollment is 302. The primary endpoint is progression-free survival in the intention-to-treat population.

The reported primary hazard ratio is 0.677, with a 95% confidence interval of 0.515 to 0.889 and p = 0.005. Median progression-free survival is 6.6 months for UFOX plus cetuximab and 8.2 months for FOLFOX4 plus cetuximab. The registry also reports best overall response and overall survival, with less conclusive evidence for a difference in the latter. The study is described as exploratory; original design assumptions, multiplicity procedures, and several secondary numerical results are not reported in the registry record.