Phase II Metronomic Dosing, Etoposide, Cyclophosphamide, D0 Prostate Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase II Metronomic Dosing, Etoposide, Cyclophosphamide, D0 Prostate Cancer (NCT00176605), a na phase 2 study. The primary outcome is PSA Response Rate.

2. Clinical Question

The protocol summary frames the study around a hypothesis about timing: using etoposide and cyclophosphamide earlier in the course of prostate cancer progression, when fewer tumor cells are present, might have greater anti-tumor activity. The study was intended to assess toxicity as well as anti-tumor activity. That statement describes the rationale and hypothesis, not a finding from the trial.

Because the design is single-group, the primary question is descriptive: whether participants in this treated group met the registry’s response definition. It is not a randomized comparison of the regimen against another treatment or against no treatment. The registry record does not report the observed PSA response rate, so the response question cannot be answered from the posted results in this record.

3. Trial Design

The registry identifies this as a Phase II study with a single-group model and no masking. Allocation is listed as NA. The study is marked completed, with an enrollment of 15. Its condition is prostate cancer, and the official title specifies patients with stage D0 prostate cancer. The sponsor is Rutgers, The State University of New Jersey. The recorded start is 2005-05 and primary completion is 2008-10.

The intervention group is titled Arm 1 (Etoposide + Cyclophosphamide). The arm description says therapy was divided into 4 cycles, each composed of 6 weeks of therapy, for a total duration of 24 weeks. Etoposide and cyclophosphamide are each listed at 50 mg po qd, alternating in 21-day intervals and starting with etoposide. The posted arm description ends while describing the first interval, so the remainder of the administration details is not reported in the registry record.

The registry lists PSA response rate as the primary outcome, expressed as a percentage of participants, with a timeframe of 5 years. A secondary outcome concerns toxicities related to chronic administration of the two drugs. The record lists two outcome measures, but it does not provide a primary response result or a detailed account of the outcome analysis.

This design can describe outcomes observed in the treated group, but without a separate comparison group it cannot isolate the regimen’s effect from other explanations for outcomes over time. The record does not report a formal statistical analysis plan, a sample-size justification, or details of any interim analyses. These items should not be inferred from the Phase II label or from the treatment schedule.

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 PSA Response Rate, measured over 5 years.

The primary endpoint is the PSA response rate, defined in the registry as the percentage of participants with a PSA decline of at least 50%. The decline must be confirmed by a second PSA value four or more weeks later. The reference PSA is to be measured within 2 weeks before therapy begins, and participants must not demonstrate clinical or radiographic evidence of disease progression during the response period. The stated timeframe is 5 years.

This definition combines a threshold change with confirmation over time and a restriction related to progression. Confirmation can help distinguish a sustained decline from a single measurement that might not reflect a persistent response. Requiring the reference measurement close to therapy initiation establishes the baseline for assessing the change. These are general reasons why an endpoint definition may specify baseline timing and confirmation; the registry does not give a separate rationale for choosing this particular definition.

A PSA response rate is a binary-outcome summary at the participant level: each participant either meets the registry’s response criteria or does not. The resulting percentage describes the proportion meeting that definition in the study group. It does not, by itself, quantify how long a response lasts, establish a causal treatment effect, or substitute for other clinical outcomes.

The registry record does not report the observed response count or percentage, an uncertainty interval, or a statistical test for this endpoint. As a result, the endpoint definition is available, but the actual PSA response result and its precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a single-group Phase II study with no masking. This design places the emphasis on observing outcomes in a group receiving the listed regimen. It does not create a randomized comparison. The distinction matters because a within-group outcome and a treatment effect relative to a comparator are different statistical questions. A response rate can summarize the former; estimating a comparative effect generally requires an appropriate comparison and analysis.

What does a percentage endpoint represent?

The primary endpoint is defined as a percentage of participants who meet a specified response rule. For a binary endpoint, each participant is classified according to whether the criteria are met. The response rate is the proportion classified as responders, expressed as a percentage. This kind of summary is easy to interpret, but its meaning depends on the exact definition, the analysis population, and the handling of participants whose response status is unknown. The registry describes the response criteria but does not report the observed response result, the analysis population, or how missing response assessments were handled.

Why require confirmation?

The registry requires a PSA decline of at least 50% to be confirmed by another PSA value four or more weeks later, and it specifies a reference measurement within 2 weeks before therapy. In general, repeat confirmation can reduce the chance that a response classification rests on a transient or atypical measurement. The baseline timing also makes the comparison point explicit. These are general statistical and measurement considerations; the registry does not report a specific analysis rationale for each part of the endpoint definition.

What would an uncertainty interval add?

In general, a confidence interval expresses the precision of an estimated quantity under the assumptions of the statistical method used. For a response percentage, it would show a range of values compatible with the data and method, rather than presenting the estimate as exact. A narrower interval indicates greater precision under those assumptions; a wider interval indicates less precision. A confidence interval does not correct for bias, create a comparison group, or establish causation. No response estimate or confidence interval is reported in the registry record, so no such precision assessment can be made from its primary outcome entry.

What does the absence of a comparator imply?

In a randomized comparative study, random assignment can support a between-group interpretation by balancing factors across groups in expectation. This trial is not described as randomized and has a single treatment group. General statistical reasoning therefore cautions against treating an observed outcome in that group as a controlled estimate of what the regimen caused. Changes over time, differences in underlying risk, measurement patterns, and other influences may contribute to outcomes. The registry record does not give a control-group result to contrast with the treated group.

How should the planning illustration be understood?

Any sample-size values associated with an observed effect are planning illustrations, not observed power. The stated assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Such assumptions describe a hypothetical planning exercise. They do not establish that these calculations formed the trial’s original design or that they apply to this single-group study. The registry record does not report the trial’s own sample-size justification or statistical plan. A two-arm planning framework should not be read as evidence that the actual study had a comparator.

What can be concluded from the safety summaries?

For binary adverse-event summaries, the number affected and the number at risk describe participants with at least one event in the relevant category, as represented by the registry. The percentage is a participant-level proportion, not necessarily a count of all individual events. General caution is needed because one participant may experience more than one event, and a serious-event category may not represent the same thing as a broader adverse-event summary. The record lists affected and at-risk counts but does not provide enough event-level information to reconstruct timing, repeated events, or overlap between categories.

What statistical plan is documented?

The registry record reports zero analysis records. It does not report the model, test, uncertainty method, prespecified subgroup analyses, adjustment strategy, or analysis population for the primary outcome. It also does not report interim analyses. These omissions mean that readers cannot assess whether a particular method was prespecified, how deviations were handled, or whether the analysis matched an original plan. A method should not be inferred solely from the endpoint format or the study phase.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Arm 1 (Etoposide + Cyclophosphamide)")
n      <- c(13)
events <- c(2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Arm 1 (Etoposide + Cyclophosphamide)  13  2  15.4  1.9  45.4  4.3  42.2  4.7  42.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists PSA response rate as the primary outcome and toxicity related to chronic administration as a secondary outcome. It also lists two outcome measures, but does not report a detailed statistical analysis for them. The record reports zero analysis records. It does not state whether the outcomes were tested formally, whether there were additional planned comparisons, or whether any multiplicity adjustment was used. Therefore, the approach to controlling the chance of false-positive findings across multiple tests is not reported in the registry record.

Missing-data handling is also not reported in the registry record. The primary endpoint requires a confirmed response assessment, but the record does not say how participants without a confirmation value, without a suitable baseline measurement, or with incomplete follow-up were classified. It does not report whether the analysis used an intention-to-treat population, an evaluable population, or another population definition. These choices can affect a response percentage and its interpretation.

The registry’s enrollment figure does not, on its own, establish the number included in the primary endpoint analysis. The record does not report exclusions, withdrawals, or the number with outcome assessments. No assumptions about missingness or imputation can be inferred. Consequently, neither the analysis denominator nor the sensitivity of the result to missing data can be assessed from the registry record.

12. 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: valvular heart disease (6.7%), ulcer, gi - anus (6.7%), infection with unknown anc - appendix (6.7%).

The registry reports serious adverse events for Arm 1 (Etoposide + Cyclophosphamide): 3 affected participants among 15 at risk. For other adverse events, it reports 11 affected participants among 15 at risk. These are participant counts in the posted summaries, not necessarily counts of every event experienced. A participant may have experienced more than one event, and the registry does not report whether the serious and other adverse-event groups overlap.

The listed serious-event terms are valvular heart disease, Ulcer, GI - Anus, and Infection with unknown ANC - appendix. Each term has a reported value of 6.7%. The registry does not provide event-level details such as timing, duration, recurrence, severity grading, or attribution. The figures should therefore be read as the registry’s recorded safety summaries, not as a complete account of every safety dimension or a comparison with another treatment.

The record does not report a comparator group, so these figures cannot be interpreted as comparative risk estimates. They describe events recorded in the treatment group only.

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

The registry record answers some descriptive questions about the study: it identifies a single-group Phase II design, names the drugs, specifies the intended treatment schedule, defines the PSA response endpoint, and reports selected safety counts. It also states that the study was completed. These details establish what the study was intended to examine and what safety information was recorded.

The record does not report the primary PSA response rate or the number of participants who met the response definition. It therefore does not establish the magnitude or precision of the primary outcome. The study’s stated hypothesis about earlier use is a rationale to be tested, not a result. Without a reported outcome estimate, readers cannot determine from this record how the study’s observed response aligned with that hypothesis.

Even if a response percentage were available, a single-group study would describe outcomes in the treated group rather than provide a randomized estimate of the difference between treatments. A response in a group does not by itself establish that treatment caused the response. The absence of a separate comparator also limits interpretation of the safety counts: they do not show how those figures compare with another treatment or with an untreated group.

The reported serious and other adverse-event counts should be interpreted within the registry’s stated denominators and categories. The limited event detail does not permit conclusions about timing, repeated events, or overlap. Likewise, the absence of a reported analysis population and missing-data approach means the primary outcome denominator cannot be verified from the registry record.

In short, the record documents a completed study and its intended outcome criteria, alongside selected safety summaries. It does not report the central efficacy result, its uncertainty, or a controlled comparison. Those limits prevent stronger statistical conclusions from being drawn from this registry entry alone.

14. Why This Trial Matters Statistically

This study illustrates how a trial can have a clearly defined clinical question while leaving important statistical evidence unavailable in its registry record. The PSA response definition specifies a threshold decline, confirmation, a baseline window, and the absence of clinical or radiographic progression during the response period. Clear endpoint rules are important because they make explicit what counts as an outcome rather than leaving classification to informal judgment.

At the same time, a well-defined endpoint is not the same as a reported result. The registry gives the response criteria but not the number of responders, the response percentage, or an uncertainty interval. Without those quantities, the endpoint cannot be evaluated as an observed finding. This distinction is fundamental when interpreting clinical trial records: protocol intent and outcome reporting are different forms of information.

The single-group structure also highlights the difference between describing an outcome and estimating a comparative effect. A treated-group response rate can be informative as a description, but it does not by itself show what would have happened under an alternative. Statistical interpretation must reflect the design rather than imply a comparison that the study did not include.

Finally, the record shows why transparency about analysis populations, missing data, and multiplicity matters. Without those details, readers cannot fully evaluate how outcomes were classified, what data contributed to an estimate, or how multiple outcomes were treated. The registry entry offers useful design and safety context, but its missing primary result and analysis details sharply limit what can be concluded statistically.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several limitations are specific to the information in this registry record. Most importantly, the primary endpoint result is not reported. The registry gives the PSA response definition and timeframe, but no response count, percentage, or uncertainty estimate. This prevents assessment of the primary outcome itself.

The study has a single-group design, with allocation listed as NA and no separate comparator described. As a result, the record does not support a between-group treatment comparison. The enrollment figure does not establish how many participants contributed to the primary endpoint analysis; the analysis denominator and population are not reported.

The record does not report how missing or unconfirmed PSA assessments were handled, whether participants withdrew or were excluded, or whether the endpoint was analyzed according to a prespecified population. It also does not report the statistical method, multiplicity strategy, interim analyses, or original sample-size justification. The posted arm description ends before completing the account of the alternating administration schedule, so the full treatment details are not available in the registry record.

The safety summaries provide affected and at-risk counts and selected serious-event terms, but not event-level information about timing, duration, recurrence, severity grading, attribution, or overlap between categories. These gaps limit detailed interpretation of both efficacy and safety. They are limitations of what the registry record reports; the record does not establish whether additional information exists elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase II Metronomic Dosing, Etoposide, Cyclophosphamide, D0 Prostate Cancer — NCT00176605.
• Registry record last updated 2014-05-20; status last verified 2014-04.
• Results first posted 2014-05-20.
• 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.

19. Record Summary

NCT00176605 is a completed Phase II, single-group study of etoposide and cyclophosphamide in patients with stage D0 prostate cancer. The registry lists an enrollment of 15, no masking, and no separate comparator group. The primary outcome is PSA response rate, defined by a confirmed decline of at least 50% and the absence of clinical or radiographic progression during the response period.

The record reports serious adverse events in 3 participants among 15 at risk and other adverse events in 11 participants among 15 at risk. It lists three serious-event terms, each reported at 6.7%. The primary PSA response result, analysis population, missing-data approach, and statistical analysis are not reported in the registry record. Interpretation is consequently limited to the design, endpoint definition, and posted safety summaries.