Therapy With Topotecan and Carboplatin by Patients With Relapsed Ovarian Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Therapy With Topotecan and Carboplatin by Patients With Relapsed Ovarian Cancer (NCT00170625), a non-randomized phase 1, phase 2 study. The primary outcome is Occurrence of a DLT (Dose Limiting Toxicity).

2. Clinical Question

The study concerns people with relapsed ovarian cancer and examines compatibility of topotecan given in combination with carboplatin. The registry divides participants into groups according to the interval since relapse: 6–12 months and >12 months. These groups are not randomized treatment arms, and the record cautions that they are not a like-for-like control comparison.

The primary question is about tolerability under the specified regimen, rather than a randomized comparison of treatment effects. The listed secondary outcome is progression-free survival, but the registry record does not report its results. Nor does it give a result count for the primary endpoint. As a result, the clinical question can be described from the study plan, but the posted record does not establish how frequently the defined toxicity occurred or how progression-free survival was characterized.

3. Trial Design

This is a completed, multicenter, prospective phase I/II study sponsored by the North Eastern German Society of Gynaecological Oncology. The registry lists the study start as 2004-06 and primary completion as 2005-08, with enrollment of 28. Allocation is nonrandomized, masking is none, and the model is single group. The record nevertheless presents two relapse-interval groups; it explicitly cautions against treating them as a like-for-like control comparison.

The intervention is Hycamtin, the listed drug, with arm descriptions specifying topotecan and carboplatin. At dose level 0, the described regimen is topotecan 1mg/m2/d on day 1-3, q 21d, with carboplatin AUC 5 on day 3 after topotecan application. The descriptions say that if dose-limiting toxicity is present, topotecan will be reduced to dose level -1, specified as 0.75 mg/m2/d on day 1-3, q 21d. The carboplatin schedule is also described in the registry, although the arm-description text is incomplete.

The primary endpoint is occurrence of a dose-limiting toxicity after each cycle for up to one year. Progression-free survival is listed as a secondary outcome. The registry record does not report a randomization procedure, concealment, blinding, a sample-size justification, or further details of the phase I/II structure. It also does not report an analysis of either endpoint. The record’s status is completed, but completion status alone does not indicate that outcome results were posted.

Because treatment allocation was not randomized and the groups are based on relapse interval, differences between those groups could reflect differences other than treatment. The design therefore does not support interpreting a contrast between the groups as a randomized estimate of treatment effect. The available record is best read as a description of the planned regimen and endpoint, together with the limited posted safety counts.

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: 2 patients missed the inclusion criteria

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.

6. Primary Endpoint

The registry lists the primary outcome as Occurrence of a DLT (Dose Limiting Toxicity), measured over after each cycle for up to one year.

The primary endpoint is occurrence of a dose-limiting toxicity, counted as participants. The registry defines a dose-limiting toxicity as a postponement due to hematologic toxicity of more than 7 days within the first four courses at dose level 0. The outcome timeframe is after each cycle for up to one year.

This endpoint is used in a phase I/II treatment study to describe a prespecified tolerability event under the treatment regimen. A clear operational definition matters: it identifies the type of toxicity, the length of postponement, and the treatment period that qualifies. The definition is narrower than a general count of all adverse events, since an event must meet the specified hematologic-toxicity and postponement criteria.

The registry’s primary-outcome entry gives the definition and timeframe, but it does not give the number of participants who met the definition, a denominator for an analyzed population, or an uncertainty estimate. It therefore does not show the observed frequency of the primary endpoint. The separate serious adverse-event counts should not be substituted for this endpoint: they describe serious-event reporting, not necessarily the specifically defined dose-limiting toxicity. The registry record also does not report how the endpoint was handled if a participant did not complete the first four courses or had incomplete follow-up.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The available statistical information is limited. The registry identifies a participant-count endpoint, a toxicity definition, a timeframe, and progression-free survival as a secondary outcome. It lists zero analyses. It does not report a statistical analysis plan, endpoint estimates, uncertainty intervals, or tests. The distinctions below explain what these methods ordinarily mean; they do not imply that a particular method was used in this study.

What does a participant count describe?

A count of participants with an event is a direct summary of how many people met a defined outcome. To interpret that count as a frequency, a reader also needs the relevant denominator: the number of participants whose outcome could be assessed under the stated definition. The registry identifies the endpoint unit as participants, but it does not report the number who met the primary definition or an analysis population for that endpoint. The safety entries give at-risk and affected counts, but they do not fill in the missing dose-limiting-toxicity result.

For general statistical context, a proportion estimates the share of an eligible group with an event. Uncertainty around that estimate reflects that the observed participants are not the only possible participants who might have received the regimen. A confidence interval communicates that sampling uncertainty. Without the endpoint count and corresponding analysis denominator, neither a primary-endpoint proportion nor its uncertainty can be interpreted from this record.

Why is the endpoint definition important?

The primary endpoint is not an unrestricted tally of toxicity. It requires a postponement attributed to hematologic toxicity, lasting more than 7 days, within the first four courses at dose level 0. A definition tied to the event type, duration, treatment level, and observation period makes outcome classification more consistent. It also limits what the endpoint captures: other adverse effects, or postponements that do not meet the stated conditions, do not necessarily count as this endpoint.

The listed follow-up is after each cycle for up to one year. Repeated assessment over treatment cycles can raise analysis questions, such as how to handle participants with differing numbers of cycles or incomplete follow-up. The registry record does not report how these issues were addressed. It would be inappropriate to infer a rule for missing cycles, discontinuation, or changes in dose.

What does nonrandomized grouping imply?

Random assignment is a general method for balancing measured and unmeasured characteristics between treatment groups, on average. This record states that allocation was nonrandomized and the model was single group, while also describing groups by relapse interval. The registry explicitly warns that these groups are not a like-for-like control comparison. Their counts can be described, but a contrast between them cannot be interpreted as if participants had been randomly assigned to interchangeable arms. Differences in the groups may reflect participant characteristics or other circumstances that the record does not describe.

Masking is listed as none. Masking is a design feature intended to limit the influence of knowledge of treatment assignment on assessment or care. The record does not give further details about outcome assessment, so no more specific inference about ascertainment can be made.

How should progression-free survival be understood?

Progression-free survival is a time-to-event outcome. In general, such outcomes consider both whether an event occurred and when it occurred, and may require methods that account for participants whose event time is not observed during follow-up. The registry lists progression-free survival as a secondary outcome but does not report an estimate, event count, follow-up summary, censoring approach, or analysis method. No time-to-event result can therefore be interpreted from this record.

What does the planning illustration represent?

The registry describes a planning illustration computed from an observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It states that the effect to detect is a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial was designed with those assumptions. The registry record does not report the trial’s own sample-size justification.

For general statistical context, a sample-size calculation estimates how many participants would be needed under specified assumptions to detect an effect with a chosen operating characteristic. Such a calculation depends on the assumed effect and analysis method. A post hoc illustration based on an observed effect is not observed power and does not establish that a study’s findings are reliable. The record also distinguishes illustrations for time-to-event outcomes, which use a total event count, from other outcomes, which use participants per arm. No resulting sample-size values are reported in the registry record for this analysis, so none should be inferred.

Why can over-dispersion matter?

For general statistical context, over-dispersion occurs when variation in the data exceeds what a statistical model assumes. If a model ignores excess variation, its uncertainty estimates can be too small and tests can appear more decisive than the data warrant. The posted primary endpoint is a participant count and the record does not report a model-based analysis or dispersion parameter. Over-dispersion is therefore a general consideration, not a reported feature or method of this study.

Overall, the registry describes enough to understand the intended primary endpoint and broad study structure, but not enough to reconstruct an analysis. The absence of a reported analysis plan, endpoint count, and outcome estimates is central to interpreting the record.

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("Relapse 6-12 Months", "Relapse >12 Months")
n      <- c(13, 13)
events <- c(0, 1)
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  Relapse 6-12 Months  13  0  0.0  0.0  24.7  0.0  22.8  0.2  23.2
ARM  Relapse >12 Months  13  1  7.7  0.2  36.0  1.4  33.3  1.8  33.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome, occurrence of dose-limiting toxicity, and one secondary outcome, progression-free survival. It reports two outcome measures, but lists zero analyses. No statistical analysis plan, testing hierarchy, adjustment for multiple comparisons, or interim analysis is reported in the registry record. It is therefore not possible to determine whether the investigators planned multiple tests, how they would control the chance of false-positive findings across outcomes, or whether any interim looks at accumulating data occurred.

For general statistical context, multiplicity arises when several outcomes, comparisons, time points, or analyses are examined. Testing many hypotheses can increase the chance that at least one result appears notable by chance. A prespecified hierarchy or adjustment can address this, but neither should be assumed in the absence of a reported plan. Since no endpoint analyses are posted, multiplicity cannot be evaluated from results either.

The registry record does not report missing-data counts, withdrawals, the number completing treatment, or the analysis populations used. It also does not explain how incomplete cycles, loss to follow-up, or participants without an assessable endpoint were handled. These details matter because the denominator for a participant-level toxicity frequency and the handling of incomplete observation affect interpretation. Progression-free survival would additionally require information about event ascertainment and censoring. The record contains no reported methods for these matters.

Enrollment of 28 is not, by itself, an analysis denominator for each outcome. The serious adverse-event entries report 13 participants at risk in each relapse-interval group, but those counts do not establish the population included in the primary-endpoint or progression-free-survival analyses. No assumptions about missing outcomes or analysis populations can be made from the registry record.

12. 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: thrombocytopenia (30.8%), anemia (15.4%), allergic reaction (7.7%).

The registry lists serious adverse-event counts separately for the relapse 6–12 months and relapse >12 months groups. Each group has 13 participants at risk, with 6 affected by serious events. The record also lists other adverse-event counts: 10 among 13 at risk in the first group and 7 among 13 at risk in the second. It lists 4 deaths in each group. These are descriptive entries and do not show that the groups are comparable or that any event was caused by treatment.

The listed leading serious-event terms are thrombocytopenia at 30.8%, anemia at 15.4%, and allergic reaction at 7.7%. The record does not specify the denominator, group attribution, event timing, or whether these percentages refer to participants or events. They should not be treated as group-specific risks or compared with the affected counts without additional information.

Serious adverse events are not interchangeable with the primary endpoint. The primary endpoint requires a specific postponement due to hematologic toxicity, with a defined duration and treatment period. The serious-event counts may include events that do not meet that definition, and the registry does not report the overlap. It also does not give causes or timing for the deaths. These entries describe what the registry records, not a causal safety estimate.

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

The record establishes that a prospective, multicenter phase I/II study examined topotecan with carboplatin for relapsed ovarian cancer and specified dose-limiting toxicity as its primary endpoint. It also gives the operational definition of that endpoint and lists progression-free survival as secondary. This information clarifies what the study set out to assess.

It does not establish the frequency of the defined dose-limiting toxicity. The registry record does not report the primary endpoint count, its denominator, an estimate, or an uncertainty interval. It likewise does not report progression-free survival results. Therefore, the posted outcome information cannot show the magnitude or precision of either endpoint’s results.

The serious-event counts and listed event terms provide limited descriptive safety information. They do not establish a causal relationship to the regimen, and the groups defined by relapse interval are not randomized controls. The record itself cautions that these groups are not a like-for-like comparison. Counts from those groups should not be treated as comparative evidence about treatment effects or differences in risk.

For general statistical interpretation, absence of a reported result is not equivalent to a result showing no events or no effect. It means the registry entry does not permit that result to be assessed. Similarly, a completed status and an enrollment count do not substitute for an outcome analysis. Any conclusion about effectiveness, safety relative to another treatment, or the precision of an estimate would require information not reported in the registry record.

The appropriate scope of interpretation is therefore narrow: the record documents the study design, the intended regimen, the primary endpoint definition, and selected adverse-event counts. It does not provide an analyzed estimate answering the primary clinical question.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between a clearly defined endpoint and a reported endpoint result. The registry defines dose-limiting toxicity with a specific event type, duration, treatment level, and observation window. That operational clarity helps identify what would count as an event. But without the event count and the analysis denominator, the definition cannot be converted into a frequency or an estimate of uncertainty.

The record also illustrates why study groups should be interpreted in light of allocation. Although the registry describes relapse-interval groups, allocation is nonrandomized and the study model is single group. The registry explicitly says the groups are not a like-for-like control comparison. This limits what can be inferred from differences in their descriptive counts and prevents a simple causal interpretation.

Another statistical lesson is that a completed study does not necessarily have posted outcome analyses. The record lists enrollment and completion status, but no primary or secondary outcome analysis. Without results, readers cannot assess precision, distinguish a small estimated event frequency from a larger one, or determine whether estimates are compatible with a range of values.

The registry’s planning illustration is also distinct from the trial’s own design. It is described as a calculation based on an observed effect and specified assumptions. Such planning illustrations can help show how sample requirements depend on assumptions, but they do not represent observed power and do not replace the missing outcome estimates. In this record, the trial’s own sample-size justification is not reported.

Together, these features make the record useful for understanding how design, endpoint definition, allocation, analysis reporting, and precision are separate parts of statistical interpretation. The limitations are not just about the size of the study; the central issue is that the primary result and its uncertainty are not reported.

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.

The principal limitation is that the registry record does not report the primary endpoint result, despite giving a detailed definition and timeframe. There is no count of participants meeting the dose-limiting-toxicity definition, no analysis denominator, and no estimate of precision. The secondary progression-free survival outcome is also listed without a result or analysis.

The design is nonrandomized, with no masking and a single-group model. The two relapse-interval groups do not form a randomized control comparison; the registry specifically warns that they are not like-for-like. Any descriptive differences between them may reflect differences not described in the record. The record does not report further participant characteristics or adjustment methods that could clarify such differences.

Safety information is incomplete for comparative interpretation. Counts are listed for serious events, other adverse events, and deaths, but the record does not give event timing, causes of death, group attribution for the listed serious-event terms, or the denominators underlying the reported percentages. Nor does it report overlap between serious adverse events and the primary endpoint.

Important methods details are not reported in the registry record, including a statistical analysis plan, sample-size justification, analysis populations, missing-data handling, interim analyses, and any multiplicity strategy. The regimen descriptions also contain incomplete text after the dose-reduction details, limiting how fully the carboplatin schedule can be reconstructed from the record. These gaps constrain interpretation of both the intended methods and the posted safety information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Therapy With Topotecan and Carboplatin by Patients With Relapsed Ovarian Cancer — NCT00170625.
• Registry record last updated 2024-11-12; status last verified 2024-11.
• Results first posted 2017-02-06.
• 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

This completed multicenter, prospective phase I/II study enrolled 28 participants with relapsed ovarian cancer. It was nonrandomized, unmasked, and listed as a single-group study, with relapse-interval groups that the registry cautions are not like-for-like controls. The intervention was Hycamtin, described as topotecan with carboplatin.

The primary endpoint was occurrence of dose-limiting toxicity, defined as a postponement due to hematologic toxicity of more than 7 days within the first four courses at dose level 0. Progression-free survival was listed as a secondary outcome. The registry record does not report analyses or results for either endpoint. It does list serious and other adverse-event counts, deaths, and leading serious-event terms, but these are descriptive and have important attribution and denominator limitations.

The posted information supports interpretation of the study’s broad design and endpoint definition, but not an estimate of the primary outcome or its precision.