Neuroprotective Effects of Lithium in Patients With Small Cell Lung Cancer Undergoing Radiation Therapy to the Brain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Neuroprotective Effects of Lithium in Patients With Small Cell Lung Cancer Undergoing Radiation Therapy to the Brain (NCT01553916), a na phase 1, phase 2 study. The primary outcome is Safety of Lithium Carbonate as Measured by Number of Patients in the Safety lead-in Who Experienced a Dose-limiting Toxicity (DLT).

2. Clinical Question

The broader rationale was concern that PCI can cause short-term memory problems by damaging the hippocampus, and the trial examined lithium as a possible neuroprotective agent. The listed secondary outcomes covered immediate and delayed recall on the Hopkins Verbal Learning Test, quality of life measured with EORTC questionnaires, and feasibility of serial cognitive and quality-of-life testing. Those questions describe the scope of the study, not evidence of an observed benefit. Results for these outcomes are not reported in the registry record.

3. Trial Design

This was a completed Phase I/II trial sponsored by Washington University School of Medicine. The registry describes a single-group model, allocation as not applicable, and masking as none. Enrollment was 19. The trial started on 2012-04-26, and primary completion was recorded as 2016-09-12. These design features are important to interpretation: the study does not include a concurrently assigned control group in the registry record, so it cannot directly estimate a treatment contrast against PCI without lithium.

Participants received lithium carbonate with prophylactic cranial irradiation. The regimen began with lithium 300 mg by mouth twice daily for 7 days before PCI and continued during PCI. PCI was scheduled to begin on Day 8, with radiation at 2.5 Gy per fraction, 5 days per week, for 2 weeks, to a total dose of 25 Gy. The registry summary describes the clinical purpose of PCI as preventing brain metastases from returning and identifies short-term memory problems as a concern.

The primary outcome was a safety measure focused on dose-limiting toxicity in the safety lead-in. Only participants enrolled in that lead-in were evaluable for the primary outcome, rather than necessarily everyone enrolled in the trial. The total number in that evaluable group and the observed DLT count are not reported in the registry record. Although the primary outcome description sets a safety threshold based on the first 6 treated, the registry does not state whether the threshold was met.

The listed secondary outcomes include immediate recall and delayed recall measured with the Hopkins Verbal Learning Test, quality of life measured with EORTC questionnaires, and feasibility of repeated neurocognitive and quality-of-life assessments. The registry lists 14 outcome measures, but it reports no analyses. It does not describe a randomized comparison, an untreated or standard-treatment control arm, or masking. Therefore, the design should be read as an early-phase, single-group evaluation rather than as a controlled estimate of the effect of lithium.

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:

Analysis population for the primary outcome, as defined in the registry: -Only patients enrolled in the safety lead-in were evaluable for this outcome measure

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 Safety of Lithium Carbonate as Measured by Number of Patients in the Safety lead-in Who Experienced a Dose-limiting Toxicity (DLT), measured over 3 weeks.

The primary endpoint counts the number of participants in the safety lead-in who experienced a dose-limiting toxicity during the stated timeframe of 3 weeks. Toxicities were to be graded and described using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v 4. The registry defines safety as fewer than 2 patients experiencing DLTs among the first 6 treated. The observed count and the number of participants actually evaluable for this endpoint are not reported in the registry record.

A toxicity count is relevant in an early-phase study because it records whether participants experienced harms serious enough to meet the protocol’s dose-limiting definition. It is a count, not a comparative effect estimate: on its own, it does not show how toxicity would differ from another treatment or from PCI without lithium. General statistical interpretation also depends on the population counted, how events were defined and assessed, the observation period, and how missing safety information was handled. The record specifies the safety-lead-in population and grading system, but does not report the detailed DLT criteria, the observed count, or missing-data handling.

The primary endpoint is distinct from the listed memory and quality-of-life outcomes. Those secondary outcomes address possible cognitive and patient-reported effects, but the registry record does not report their results. Thus, the primary safety question cannot be answered from the posted results, and the secondary outcomes cannot be used to infer that lithium prevented memory decline.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Clinical trial methods determine what a result can support. For this study, the central design fact is the single-group model. General statistical explanation: a comparison between groups can help separate differences associated with treatment from differences that might have occurred for other reasons. When a study has no concurrent control group, that separation is not available through a randomized between-group contrast. The registry records allocation as not applicable and masking as none, and does not list a comparator arm.

What does the primary count measure?

The primary outcome is a count of participants in the safety lead-in who experienced a DLT during a 3-week timeframe. The record says toxicity was graded and described using NCI CTCAE v 4. It defines safety as fewer than 2 patients experiencing DLTs among the first 6 treated. This rule is a decision threshold stated in the outcome description; it is not the reported outcome itself. The registry does not report the observed DLT count or the number evaluable for the primary endpoint. Thus, it is not possible to compare the observed count with the stated threshold using the registry record.

General statistical explanation: event counts are easiest to interpret when the event definition, follow-up window, and population at risk are clear. A count without its denominator can be difficult to contextualize; a denominator without information about follow-up and missing assessment can also be incomplete. Here, the record identifies the safety-lead-in population and timeframe but does not report the number of lead-in participants evaluable or the primary count. It also does not report detailed DLT criteria beyond the grading system and the stated threshold.

How should the adverse-event counts be read?

The registry reports 19 participants at risk and 0 affected in the serious-event category, alongside 19 at risk and 19 affected in the other-event category. These are descriptive counts. General statistical explanation: categories that use different event definitions should remain separate, and a count of participants affected does not communicate event severity, duration, recurrence, or attribution unless those details are also reported. The record does not provide serious-event terms, other-event terms, or a death count; the deaths field is null.

What would an effect estimate and confidence interval add?

General statistical explanation: an effect estimate describes the size and direction of a difference or association, while a confidence interval conveys uncertainty around that estimate. A narrow interval generally indicates greater precision than a wide interval, but the interval’s interpretation depends on the design and analysis. The registry record contains no reported analyses for the primary outcome and no effect estimate or confidence interval for the listed outcomes. As a result, there is no reported interval from which to judge precision, and the observed data cannot be used to characterize the magnitude of a cognitive or quality-of-life effect.

Why are the planning assumptions not trial results?

The stated assumptions for the sample-size illustrations are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a fraction of the observed effect. These are planning assumptions, not observed findings and not the trial’s own design description. The registry describes this study as single-group, rather than an equal-allocation comparison between two arms. It reports no analyses and no observed effect estimate on which a trial-specific illustration could be interpreted. The planning figures, if considered alongside the posted material, are illustrations only and should not be called observed power or treated as evidence that the study detected an effect.

General statistical explanation: power is a property of a specified design, sample size, outcome variability, and effect size under chosen assumptions. It is not a probability that a particular finding is true, and a post hoc calculation based on an observed effect does not substitute for a prespecified design justification. The registry does not report the protocol’s sample-size justification, the detailed statistical analysis plan, or interim analyses. Those features cannot be inferred from the trial’s phase designation or from the stated planning assumptions.

Why do outcome definitions and analysis populations matter?

The registry lists 14 outcome measures, including immediate recall, delayed recall, quality of life, and feasibility of serial testing. The primary safety outcome has a restricted evaluable population: only participants enrolled in the safety lead-in. General statistical explanation: the population included in an analysis should match the question being asked, and exclusions or missing assessments can affect how representative the result is. The record does not report how many participants completed each assessment, the analysis population for each secondary outcome, or how missing observations were handled. It also does not report multiplicity procedures or the analysis methods used for the cognitive and quality-of-life measures.

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: Lithium Carbonate + Prophylactic Cranial Ir")
n      <- c(6)
events <- c(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  Arm 1: Lithium Carbonate + Prophylactic Cranial Ir  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 14 outcome measures, covering safety, memory, quality of life, and feasibility. The record does not report results or analyses for these outcomes. It also does not state whether a primary-secondary testing hierarchy was used, whether any adjustment for multiple comparisons was planned, or how the outcomes were prioritized for interpretation. These details are not reported in the registry record.

Multiplicity is a general statistical concern when many outcomes or comparisons are examined: the chance of at least one apparently notable finding can increase if results are selected from a large set of tests. This does not mean that every study must use the same adjustment. The appropriate approach depends on the prespecified questions and analysis plan, neither of which is fully described in the registry record. The presence of repeated outcome names in the registry listing does not establish how many distinct tests were conducted, particularly because the record reports no analyses.

Missing-data methods are also not reported. The registry lists feasibility of serial neurocognitive and quality-of-life testing as an outcome, but it does not give completion counts or describe how incomplete assessments were handled. It does not report imputation, sensitivity analyses, or reasons for missing data. Such methods should not be assumed.

The primary outcome population is explicitly restricted to participants enrolled in the safety lead-in. The registry does not report the size of this group or the number included in the primary analysis. Analysis populations for secondary outcomes are not reported in the registry record. These omissions limit assessment of who contributed data and whether incomplete follow-up could affect interpretation.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious-event figures list 19 participants at risk and 0 participants affected. The other-event figures list 19 at risk and 19 affected. These are separate registry categories; the “other” count should not be read as a serious-event count. The registry does not identify the event terms, number of events per participant, timing, severity details for the other category, or whether events were judged related to study treatment. Deaths are not reported in the registry record.

These adverse-event counts are distinct from the primary DLT endpoint. The primary outcome is limited to participants in the safety lead-in and uses a DLT definition, whereas the adverse-event summary is reported for the treatment arm. The record does not provide the primary DLT count or the lead-in denominator, so the serious-event figure cannot be substituted for that outcome. General statistical interpretation: zero recorded events does not establish absence of risk, particularly when the observation period and event ascertainment details are not fully available. The figures describe what the registry reports and do not establish a treatment comparison or a complete account of safety.

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

The record documents a completed Phase I/II, single-group study of lithium carbonate given with prophylactic cranial irradiation in people with small cell lung cancer. It reports overall enrollment of 19 and describes the regimen and outcomes of interest. It does not report the primary DLT count, the number evaluable in the safety lead-in, or analyses of memory, quality of life, and feasibility. Therefore, the registry information does not establish whether the primary safety criterion was met or quantify changes in the secondary outcomes.

The intended clinical question included whether lithium might help prevent or lessen memory problems associated with PCI. That rationale reflects the trial’s motivation, not a finding. The lack of a concurrent control group also limits causal interpretation: even if cognitive scores had been reported, a single-group change would not alone show that lithium caused the change. The record does not provide a comparator-based estimate, nor does it report masking.

The adverse-event summary records 0 participants affected in the serious-event category and 19 in the other-event category, each among 19 at risk. Those counts do not provide event-level descriptions, and the other-event category should not be treated as serious toxicity. Deaths are not reported in the registry record. These data can be described, but they do not establish that the regimen is risk-free.

General statistical explanation: a result should be interpreted in light of the endpoint definition, analysis population, uncertainty, missing data, and study design. In this case, key outcome results and statistical details are not reported in the registry record. The appropriate conclusion is limited to describing the study’s design, planned outcomes, and posted adverse-event counts, without claiming efficacy or a definitive safety conclusion.

14. Why This Trial Matters Statistically

This study illustrates why a registry record should be read for both its design and its reported results. The question about lithium as a neuroprotective agent is clinically motivated by concern about memory problems during PCI, but the design is single-group and the primary safety result is not reported. A study’s stated rationale and its completed status do not replace outcome data.

Statistically, the primary endpoint is a threshold-based safety count in a restricted population: participants enrolled in the safety lead-in. The record does not report either the count or the evaluable group size. This makes it impossible to determine from the registry whether the stated threshold was reached. It also illustrates that a clearly worded outcome definition is not enough to interpret a study when the observed result is missing.

The secondary outcomes show the breadth of questions considered: immediate and delayed recall, quality of life, and the feasibility of repeated testing. Yet the registry lists 14 outcome measures and no analyses. Without outcome estimates, uncertainty measures, and information about missing assessments or multiplicity, the record cannot support conclusions about cognitive effects or quality of life.

Finally, the design distinction matters for planning illustrations. The trial is described as single-group, while the stated sample-size assumptions describe an equal-allocation, two-arm comparison. Recognizing that difference prevents a hypothetical planning calculation from being mistaken for the trial design, an observed effect, or observed power. This is a useful example of how design, outcome reporting, and the limits of registry data jointly determine what can be concluded.

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 for interpretation is that the registry record does not report the primary endpoint result. It identifies a DLT threshold and says the outcome applies only to safety-lead-in participants, but does not give the observed count or the number evaluable. The record also does not report the results or analyses for the listed secondary outcomes, including the memory, quality-of-life, and feasibility measures.

The single-group design has no concurrent control group listed, and masking is recorded as none. Accordingly, the design does not provide a direct randomized comparison that could separate treatment-associated changes from other influences. The record does not report detailed protocol information that could clarify the planned analysis, including the statistical analysis plan, sample-size justification, interim analyses, or missing-data methods.

The adverse-event summary is limited in detail. It gives counts for serious and other events but no event terms or fuller descriptions; deaths are not reported in the registry record. The primary DLT endpoint and the broader adverse-event counts are not interchangeable, and the registry does not report enough information to reconcile them.

The record also does not describe the analysis population for each secondary outcome, completion of cognitive and quality-of-life assessments, or methods for addressing multiple outcomes. These omissions make it difficult to assess precision, potential bias from incomplete data, and the role of any individual outcome finding. These are limitations of what is reported in the registry record, not evidence that the corresponding methods were or were not used in the trial.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Neuroprotective Effects of Lithium in Patients With Small Cell Lung Cancer Undergoing Radiation Therapy to the Brain — NCT01553916.
• Registry record last updated 2018-07-05; status last verified 2018-07.
• Results first posted 2017-11-08.
• 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

NCT01553916 is a completed Phase I/II, single-group trial sponsored by Washington University School of Medicine. It enrolled 19 participants with small cell lung cancer and evaluated lithium carbonate given before and during prophylactic cranial irradiation. The primary outcome was the number of safety-lead-in participants experiencing DLTs during 3 weeks, with safety defined as fewer than 2 patients experiencing DLTs among the first 6 treated.

The registry reports 0 participants affected in the serious-event category and 19 affected in the other-event category, each among 19 at risk. The primary DLT result and analyses of the listed memory, quality-of-life, and feasibility outcomes are not reported in the registry record. The single-group design does not provide a concurrent control comparison.