Adjuvant HIPEC in High Risk Colon Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Adjuvant HIPEC in High Risk Colon Cancer (NCT02231086), a randomized phase 3 study. The primary outcome is Peritoneal Recurrence Free Survival at 18 Months.

2. Clinical Question

The clinical question is whether adding adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) to systemic adjuvant chemotherapy is associated with a different number of participants free from peritoneal recurrence at 18 months, compared with systemic adjuvant chemotherapy alone. The registry record describes people with colon cancer at high risk of peritoneal carcinomatosis after curative resection, specifically T4 or intra-abdominally perforated disease.

The study was randomized, with parallel groups and no masking. Its stated hypothesis was that adding HIPEC before routine systemic therapy would reduce development of peritoneal carcinomatosis relative to systemic treatment alone. The posted primary outcome is a count of participants, rather than a reported time-to-event estimate. The record does not report an adjusted estimate for this comparison.

3. Trial Design

The registry identifies this as a phase 3 randomized, parallel-group trial with no masking. The recorded enrollment is 204. The posted primary outcome lists 102 participants in the standard systemic chemotherapy group and 100 in the adjuvant HIPEC group. The registry record does not explain the relationship between the enrollment figure and the denominators listed for the outcome, so no explanation for that difference can be inferred.

The control group received standard adjuvant systemic chemotherapy, described as CAPOX or FOLFOX according to the Dutch colon cancer guideline. The intervention group received adjuvant HIPEC with systemic adjuvant treatment. HIPEC was planned simultaneously with primary tumour resection or as a staged procedure; the record describes staged timing as less than 10 days or 5-8 weeks postoperatively. The summary specifies intraperitoneal oxaliplatin with intravenous 5-FU/LV.

The primary outcome was peritoneal recurrence-free survival at 18 months, assessed using CT and CEA. For participants with normal CEA and no CT signs of peritoneal metastasis, diagnostic laparoscopy was performed only when they consented. Peritoneal staging and biopsies of suspicious lesions were used to assess recurrence in those undergoing laparoscopy.

The registry status is completed. The recorded start is 2015-03 and primary completion is 2018-09. Secondary outcomes listed include treatment-related toxicity, hospital stay, false-negative CT findings, dissemination patterns, disease-free survival, overall survival and quality of life. Seven secondary outcomes are posted. The registry record does not report the trial's original sample-size justification, detailed analysis populations or a full 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.

Overall Study

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.

Population: Intention-to-treat Baseline population

6. Primary Endpoint

The registry lists the primary outcome as Peritoneal Recurrence Free Survival at 18 Months, measured over 18 months.

The primary endpoint is the number of participants with peritoneal recurrence-free survival at 18 months. The registry describes assessment using CT and CEA. When CEA was normal and CT did not show signs of peritoneal metastasis at that time, diagnostic laparoscopy was used for participants who consented. Complete peritoneal staging was performed during laparoscopy, with biopsies of suspicious lesions; no visible lesions or negative biopsies indicated that the participant was considered free from peritoneal recurrence.

This outcome addresses the study's central question: whether peritoneal recurrence is present after curative resection and adjuvant treatment. An 18-month assessment gives a fixed time point for comparing the groups. The posted result is a count in each arm, not a Kaplan-Meier estimate or a reported hazard ratio. It therefore describes the number meeting the stated recurrence-free assessment among the outcome denominators, rather than providing a complete account of when recurrences occurred during follow-up.

Ascertainment is not identical to routine imaging alone for every participant: laparoscopy depended on normal CEA and CT findings and participant consent. The registry record does not report how many participants underwent laparoscopy, how missing or incomplete assessments were handled, or whether every participant had an endpoint assessment at the same time.

7. Results Posted in the Registry

• Adjuvant HIPEC (Open/Laparoscopic): 80.0% (80/100) versus 77.5% (79/102) on control; risk difference 2.5 percentage points (95% CI -8.7 to 13.8), risk ratio 1.03 (0.89–1.19); unadjusted two-proportion z-test p = 0.658.

8. Statistical Interpretation

9. Statistical Methods Explained

The posted primary comparison is an unadjusted comparison of two binary outcome counts: participants recorded as free from peritoneal recurrence at 18 months and the corresponding group denominators. A binary outcome places each participant in one of two categories for analysis, such as meeting or not meeting the stated endpoint. The registry gives the counts and denominators for both randomized groups and reports a risk-difference estimate, a risk ratio, an odds ratio, their intervals, and an unadjusted p-value.

What does the risk difference describe?

In general, a risk difference subtracts the outcome proportion in one group from the outcome proportion in the other. It expresses the contrast on the original probability scale. A risk difference of zero corresponds to equal outcome proportions. The posted estimate is 0.025 for the comparison of HIPEC with standard chemotherapy. Its interval extends from -0.087 to 0.138, crossing zero. This means the interval includes no difference as well as possible differences in either direction. The estimate is unadjusted, so it does not account for any covariates.

How do the ratio measures differ?

In general, the risk ratio compares the outcome proportions directly, while the odds ratio compares the odds of the outcome. A ratio of 1 represents no contrast between groups. The posted risk ratio is 1.033, with bounds 0.895 and 1.192. The posted odds ratio is 1.165, with bounds 0.593 and 2.287. Both intervals include 1. Because ratios and differences use different scales, their numerical values are not interchangeable. The registry record does not report adjusted versions of these measures.

What does the p-value contribute?

The unadjusted p-value is 0.658. In general, a p-value describes how compatible the observed data are with a specified null model, assuming that model and the analysis assumptions hold. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of an effect. It also does not tell how likely the result is to replicate. The p-value should be read with the effect estimate and its interval, which show the estimated direction and the uncertainty around it.

Why does the endpoint ascertainment matter?

The registry describes CT and CEA assessment, with diagnostic laparoscopy for participants who had normal CEA and no CT signs of peritoneal metastasis only if they consented. In general, outcome ascertainment can affect a comparison if the chance of detecting or confirming an outcome differs between participants or groups. The record does not report laparoscopy uptake by arm, the handling of unassessed participants, or whether outcome assessment was blinded. Since masking is listed as none, the trial was open label; the registry does not state whether endpoint assessors were separately masked.

The endpoint is recorded as a participant count at a specified time, rather than as a time-to-event analysis. In general, time-to-event methods use event timing and account for varying follow-up, while a fixed-time count summarizes status at the specified assessment point. No event-time distribution, censoring details, or survival-analysis estimate for the primary endpoint is reported in the registry record. The posted comparison should therefore be interpreted as the unadjusted contrast in the recorded binary endpoint, not as a hazard ratio or a full description of recurrence timing.

The trial is randomized, which is intended in general to make treatment groups comparable at allocation. Randomization does not guarantee that every baseline characteristic is balanced, and the registry record does not include baseline characteristics or details of the randomization procedure. No adjustment strategy is reported. The comparison is consequently best described as the posted unadjusted result rather than as a covariate-adjusted treatment effect.

The registry does not report the original sample-size calculation, analysis populations, missing-data methods, multiplicity adjustment, interim analyses, or detailed statistical plan. Those omissions limit assessment of whether the posted primary analysis follows the original plan and how robust it is to alternative assumptions. The available summary supports interpretation of the displayed estimates and uncertainty, but not reconstruction of analyses that are not reported.

10. Confidence Intervals and Precision

The risk-difference estimate is 0.025, with an interval from -0.087 to 0.138. The interval crosses zero, the value corresponding to no difference on the risk-difference scale. Thus, the data are compatible with a range of effects in either direction, not only with the positive point estimate. The registry record does not state the confidence level for the interval, so it is described simply as the posted interval.

In general, a confidence interval conveys uncertainty in an estimate under the assumptions of the statistical method used. A wider interval indicates less precision than a narrower one, while an interval's position relative to the null value helps show which effect directions remain compatible with the data. An interval is not a guarantee that the true effect lies within its limits, nor does it provide the probability that a particular effect is true.

The ratio estimates are also imprecise: the risk ratio is 1.033 with bounds 0.895 and 1.192, and the odds ratio is 1.165 with bounds 0.593 and 2.287. Both intervals include the ratio value of 1, representing no group contrast. The unadjusted p-value is 0.658. These results do not isolate a single direction or magnitude with high precision.

Precision is also affected by what the summary does not show. The registry record does not report missing outcome counts, event timing, or an adjusted analysis. The 18-month endpoint includes laparoscopy only for consenting participants meeting the stated imaging and CEA conditions. Those features matter when judging how completely the recorded endpoint represents recurrence status across the randomized groups.

11. 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 sample-size figures are planning illustrations based on fractions of the observed effect, not the original trial design calculation. For this binary outcome, the figures are participants per arm, not total events. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect.

At 100% of the observed effect, the illustration gives 4,046 participants per arm for 80% power and 5,415 participants per arm for 90% power. At 75% of the observed effect, it gives 7,271 participants per arm for 80% power and 9,733 participants per arm for 90% power. At 50% of the observed effect, it gives 16,535 participants per arm for 80% power and 22,135 participants per arm for 90% power.

In general, power is the chance that a planned analysis will detect an effect of a specified size under its assumptions if that effect is present. The 80% and 90% columns describe different planning targets: the higher target requires more participants for the same assumed effect. Smaller effects are harder to distinguish from random variation, so the illustrations require more participants per arm as the assumed effect becomes smaller. The curve represents this planning relationship across effect assumptions.

These figures are not observed power. They are illustrative calculations using the observed effect as a starting point and the stated assumptions. The trial's original sample-size justification and design assumptions are not reported in the registry record.

12. 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

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.775; treatment proportion p₁ = 0.800; average p̄ = 0.787.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.5788 = 1.1344.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5785 = 0.4869.
4. n = (1.1344 + 0.4869)² / (0.0255)² = 4,045.2, rounded up to 4,046 participants per arm 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
p0 <- 0.774509803921569                          # control proportion
p1 <- 0.8                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(2231086)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 4,046 (80% power), 5,415 (90% power)
 75% of observed effect: n per arm = 7,271 (80% power), 9,733 (90% power)
 50% of observed effect: n per arm = 16,535 (80% power), 22,135 (90% power)
power.prop.test: 4045.2 
Simulated power at n = 4,046 per arm: 0.798 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists the primary outcome and seven posted secondary outcomes, including toxicity, hospital stay, CT false-negative rate, dissemination patterns, disease-free survival, overall survival, and quality of life. It does not report whether or how the analyses of multiple outcomes were adjusted for multiplicity. In general, testing multiple outcomes can increase the chance of at least one apparently unusual result arising by chance. Without a stated analysis plan or adjustment method, the secondary findings should be treated as separate reported outcomes rather than as a controlled family of tests.

The record does not report interim analyses or stopping rules. It also does not provide a detailed account of the prespecified analysis population, such as whether the primary comparison used an intention-to-treat population or another set of participants. The posted denominators are 102 for standard systemic chemotherapy and 100 for adjuvant HIPEC, but the registry does not explain how these denominators relate to the recorded enrollment or whether any randomized participants were excluded from the endpoint analysis.

Missing-data handling is not reported in the registry record. This matters because the endpoint depends on assessment at 18 months and, for some participants, laparoscopy was performed only with consent after normal CEA and CT results. The record does not state how absent assessments, declined laparoscopy, withdrawal, or incomplete follow-up were classified or handled statistically.

In general, multiplicity procedures, analysis-population definitions, and missing-data methods help clarify how reported estimates were selected and which participants contributed to them. Their absence from the record limits assessment of robustness and the scope of inference. No assumptions about these methods can be made from the outcome counts alone.

14. 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: parenteral feeding (22.0%), gastroparesis (15.0%), electrolyte disorder (8.0%), urologic (8.0%), wound infection (7.0%).

The adverse-event summary lists serious adverse events affecting 46 of 102 participants in the standard adjuvant systemic chemotherapy group and 95 of 100 in the adjuvant HIPEC group. Other adverse events are listed as affecting 102 of 102 and 100 of 100, respectively. The summary lists no deaths in either group. These counts should be read as the posted group-level figures; they are not adjusted comparisons and do not by themselves establish that treatment caused a difference.

The listed serious-event terms include parenteral feeding at 22.0%, gastroparesis at 15.0%, electrolyte disorder at 8.0%, urologic events at 8.0%, wound infection at 7.0%, and paralytic ileus at 5.0%. The registry record does not identify these term percentages by treatment group in the listed summary, so they should not be attributed to one arm. It also does not specify the event-grade criteria, duration of safety follow-up, or how the terms were grouped.

In general, adverse-event counts depend on the definitions used, how consistently events are sought and recorded, and the time participants are followed. The posted figures provide a descriptive safety summary, not a causal estimate.

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

The posted primary outcome counts are 79 participants in the standard chemotherapy group and 80 in the HIPEC group meeting the stated 18-month peritoneal recurrence-free assessment. The unadjusted risk-difference estimate is positive for the HIPEC comparison, but its interval includes zero and the unadjusted p-value is 0.658. The data therefore do not provide a statistically clear separation between the groups in this posted comparison.

That interpretation is not the same as proving that the groups are equivalent. The interval extends to both sides of no difference, and the registry does not report an equivalence margin or a non-inferiority analysis. The estimate also does not establish that HIPEC is beneficial or harmful. It describes the direction and uncertainty of the observed unadjusted contrast in this trial's recorded endpoint.

The endpoint is specific to peritoneal recurrence at 18 months. It does not, by itself, describe recurrence after that assessment, distant metastases, overall survival, quality of life, or the full experience of treatment-related toxicity. Some of these outcomes are listed as secondary outcomes, but the information summarized for the primary comparison does not answer them.

The result also depends on how the endpoint was assessed. CT and CEA were used, with laparoscopy for certain participants who consented. The registry record does not report how many participants received laparoscopy or how incomplete assessments were handled. The absence of these details limits conclusions about endpoint ascertainment and missing data.

In general, a non-significant test does not show that there is no effect; it indicates that the data and analysis do not clearly distinguish the observed result from the null model. The interval is important because it shows that a range of potentially different effects remains compatible with the posted data. The result should be understood as an uncertain estimate from this randomized comparison, not as a definitive statement about treatment efficacy.

16. Why This Trial Matters Statistically

This trial raises several statistical issues common to randomized clinical research. First, the primary outcome is clinically focused but combines an 18-month status assessment with a diagnostic pathway that could include laparoscopy only for participants who consented after normal CEA and CT results. The method used to verify the endpoint can affect how confidently a count represents recurrence status.

Second, the reported effect is modest in the sense that its unadjusted interval crosses the no-difference value and remains compatible with effects in either direction. The point estimate alone is not enough to judge the strength of evidence. Reading the effect estimate, interval and p-value together avoids treating a single statistic as a complete summary.

Third, fixed-time participant counts and time-to-event summaries answer different questions. The posted primary comparison gives counts at 18 months; it does not show when recurrences occurred or account explicitly for different follow-up times. The registry record lists disease-free and overall survival as secondary outcomes, but those results are not included in the primary comparison.

Finally, the planning illustrations emphasize how strongly sample-size requirements depend on the assumed effect. They use the observed effect and stated planning assumptions, not the trial's original design justification. The record does not report that original justification, missing-data methods, analysis populations, or multiplicity procedures. Those omissions are relevant when evaluating precision, reproducibility, and how broadly the posted estimates can be interpreted.

17. 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 posted endpoint is a participant count at 18 months, and the registry record does not report event timing or a time-to-event estimate for the primary outcome. The counts therefore do not describe when peritoneal recurrences occurred or how follow-up differed across participants.

Endpoint assessment included CT and CEA, with laparoscopy for eligible participants only when they consented. The record does not report laparoscopy uptake by arm, the number of incomplete or missing assessments, or the statistical handling of those cases. This leaves uncertainty about the completeness and comparability of endpoint ascertainment.

The record lists an enrollment of 204, while the primary outcome denominators are 102 and 100. It does not explain the relationship between these figures. No baseline characteristics are included in the registry entries, and the randomization procedure is not described beyond the randomized allocation label. The primary comparison is unadjusted; covariate adjustment is not reported.

The registry record does not report the original sample-size justification, the detailed statistical plan, analysis populations, interim analyses, stopping rules, or multiplicity adjustment. The confidence level associated with the posted intervals is also not stated. These gaps limit appraisal of prespecification and the effect of missing data or multiple analyses.

The posted adverse-event summary does not specify safety follow-up duration, event-grade criteria, or treatment-group attribution for the listed serious-event term percentages. These are descriptive reporting limitations and do not permit causal conclusions from the event counts alone.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Adjuvant HIPEC in High Risk Colon Cancer — NCT02231086.
• Registry record last updated 2021-09-16; status last verified 2021-08.
• Results first posted 2021-09-16.
• 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.

21. Record Summary

This completed phase 3 trial randomized people with high-risk colon cancer to adjuvant HIPEC plus systemic chemotherapy or standard adjuvant systemic chemotherapy alone. The registry lists enrollment of 204 and a primary endpoint of peritoneal recurrence-free survival at 18 months, assessed using CT and CEA, with diagnostic laparoscopy for some consenting participants.

The posted outcome counts are 79 of 102 in the standard chemotherapy group and 80 of 100 in the HIPEC group. The unadjusted risk-difference estimate is 0.025, with an interval from -0.087 to 0.138, and p = 0.658. The interval includes zero, leaving uncertainty about the direction and size of the group difference.

The registry also lists secondary outcomes and adverse-event summaries. It does not report important analysis details, including missing-data handling, analysis populations, multiplicity procedures, or the original sample-size justification.