S0433 Iodine I 131 Tositumomab, Rituximab, and Combination Chemotherapy in Treating Older Patients With Stage II, Stage III, or Stage IV Non-Hodgkin's Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for S0433 Iodine I 131 Tositumomab, Rituximab, and Combination Chemotherapy in Treating Older Patients With Stage II, Stage III, or Stage IV Non-Hodgkin's Lymphoma (NCT00107380), a na phase 2 study. The primary outcome is Progression-free Survival (PFS) at 2 Years.

2. Clinical Question

The clinical question is about the outcome observed after the combined treatment in this study population, not about whether the regimen is better than another treatment. With no control group, the study can describe outcomes among participants treated in the trial, but it cannot isolate the effect of the combination from other explanations for those outcomes. The registry also lists a secondary outcome concerning Grade 3 through Grade 5 adverse events related to study drug. That outcome’s result is not reported in the registry record.

3. Trial Design

This was a phase II, completed, single-group study sponsored by SWOG Cancer Research Network. The registry lists enrollment as 86 and describes the population as older patients with stage II, stage III, or stage IV non-Hodgkin’s lymphoma. The official title narrows the intended population to patients age 60 or older with advanced-stage diffuse large B-cell NHL. The number of enrolled participants who met the primary analysis population definition is not reported in the registry record.

The treatment group is named “R-CHOP x 8 with I-131 Tositumomab.” Its arm description lists cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab, and tositumomab with iodine I 131. The dosing description includes rituximab on day 1 every 21 days for 6 cycles, along with chemotherapy dosing and antibody administration. No separate treatment arm or untreated control group is listed.

Allocation is recorded as NA, masking as none, and the model as single-group. Thus, this was not a randomized, masked comparison. Its design supports a description of outcomes in the treated group, rather than a direct estimate of how those outcomes differ from a control treatment. The registry dates the study start to 2005-11 and primary completion to 2013-11; its status is completed.

The registry record does not report a detailed protocol rationale for the design, a sample-size justification, or a statistical analysis plan. The available description identifies the primary outcome and the analysis population in general terms, but does not explain how the target enrollment was chosen or whether the study had planned interim analyses. Those details should not be inferred from the phase designation or the completed status.

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: All eligible patients who started treatment were included in the analysis

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: All eligible patients who started treatment were included in the analysis

6. Primary Endpoint

The registry lists the primary outcome as Progression-free Survival (PFS) at 2 Years, measured over 0-2 years.

The primary outcome is progression-free survival (PFS) at 2 years, expressed as a percentage of participants. PFS is measured from registration until the first observation of progressive disease or death from any cause. A participant known to be alive and progression-free at last contact is censored at that contact date.

The endpoint combines disease progression and death into an event measure. It therefore describes the proportion of the analysis population without either event through the stated follow-up period, subject to the registry’s censoring definition. It is not the same as response rate: a response describes tumor shrinkage or disappearance under specified criteria, whereas PFS concerns the time until progression or death.

The registry describes progression using clinical response criteria. Its definition includes specified growth in measurable disease, a new lesion or site, unequivocal progression of non-measurable disease, or death due to disease without prior recorded progression. The exact criteria and assessment process matter because they determine which observations count as events.

Time-to-event outcomes are useful when participants may be followed for different lengths of time or when some are still event-free at their last contact. Censoring retains information that a participant was known to be progression-free up to that point, without treating the subsequent unobserved period as event-free. The registry record states this censoring rule, but does not report the number censored, the observed PFS percentage, or its 95% confidence interval. The primary endpoint’s result is therefore not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary endpoint estimate?

The primary endpoint is a percentage at a specified time point: PFS at 2 years. In general, a time-to-event estimate uses the observed timing of events and the time participants remain under observation. Participants who have not had an event by their last known follow-up are censored at that time, rather than counted as if they remained event-free indefinitely. The registry states that participants last known to be alive and progression-free are censored at last contact.

General statistical explanation: censoring is a way to use partial follow-up information. It does not mean that the participant experienced progression, and it does not establish what happened after contact ended. The reliability of a time-to-event estimate depends in part on the completeness and duration of follow-up, the event assessments, and the assumptions used to handle censoring. Follow-up completeness and censoring diagnostics are not reported in the registry record.

How should a confidence interval be read?

The primary outcome is specified with a 95% Confidence Interval. In general, a confidence interval expresses statistical uncertainty around an estimate: narrower intervals indicate greater precision, while wider intervals indicate less precision. The interval is not a guarantee that the true value lies within its particular bounds. Its interpretation depends on the method used to calculate it and on the design and assumptions underlying that method.

The registry record does not report the PFS estimate or the interval bounds, and it does not identify the calculation method. Consequently, the precision of the primary outcome cannot be assessed from the registry information. A confidence interval cannot be reconstructed without the necessary outcome data and analysis details, and no such reconstruction is warranted from the endpoint description alone.

What does a single-group design allow?

General statistical explanation: a single-group study estimates outcomes among participants who received the study regimen. It does not directly estimate a contrast with an alternative regimen because there is no concurrent comparison arm. Even if an outcome percentage is reported, it describes the observed study group; differences from outcomes in other settings may reflect differences in patient characteristics, follow-up, outcome assessment, or other factors, not solely treatment.

This study is explicitly recorded as single-group, with allocation listed as NA and masking as none. The registry does not specify a comparator. Therefore, any statistical interpretation should remain descriptive rather than treating the study as a randomized treatment comparison.

What do the planning assumptions mean?

The registry’s sample-size assumptions describe planning illustrations based on an observed effect, not the trial’s own design. They specify a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect defined as a stated fraction of the observed effect. For time-to-event tables, the calculation is described as a total number of events; other calculations are described as participants per arm.

General statistical explanation: such calculations illustrate how a hypothetical comparison might be planned under stated assumptions. They do not show the trial’s actual power, do not establish that the trial enrolled enough participants to detect a particular effect, and are not observed results. The two-arm equal-allocation assumption is distinct from this study’s registered single-group design. The registry record does not report the original sample-size justification or a protocol-based power target.

Where planning illustrations are based on a fraction of an observed effect, their meaning depends on the observed effect estimate and on the assumptions used to translate that effect into a hypothetical design. The primary outcome estimate itself is not reported in the registry record. No planning figure should therefore be read as an independent confirmation of efficacy or as evidence that the study had a particular probability of finding a result.

What can adverse-event summaries tell us?

General statistical explanation: an adverse-event count describes how many participants experienced events according to the event category and observation period used in the record. It is not interchangeable with an event rate per unit of follow-up, and it does not alone indicate severity, duration, recurrence, or causation. A serious-event designation is also not the same thing as a judgment that treatment caused the event.

The registry lists a serious-event summary with 84 at risk and 8 affected, and an other-event summary with 84 at risk and 84 affected. It also lists specific serious-event terms and percentages. The registry record does not provide enough detail in the available summary to infer comparative safety or attribute individual events to the regimen. Any causal interpretation requires more than an aggregate count.

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("R-CHOP + I-131-tositumomab")
n      <- c(84)
events <- c(58)
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  R-CHOP + I-131-tositumomab  84  58  69.0  58.0  78.7  58.5  77.9  58.5  77.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures, but reports no analyses in the record. It identifies PFS at 2 years as the primary outcome and lists a secondary outcome concerning the number of patients with Grade 3 through Grade 5 adverse events related to study drug. The other outcome measures are not reported in the registry record. The result for the named secondary outcome is also not reported.

Multiplicity concerns arise when a study evaluates multiple outcomes or makes multiple statistical comparisons. In general, the more results tested, the greater the chance that at least one may appear noteworthy by chance if no adjustment or prespecified hierarchy is used. The registry record does not report a multiplicity plan, a hierarchy among outcomes beyond identifying the primary outcome, or any adjustment for multiple testing. It is not possible to conclude from the absence of these details that no such procedures were used; they are simply not reported in the registry record.

The primary population is described as all eligible patients who started treatment. The number meeting that definition is not reported in the registry record, so the enrolled count of 86 cannot be assumed to be the exact analysis denominator. The registry defines censoring for participants last known to be alive and progression-free at last contact. It does not report additional missing-data methods, the amount of missing outcome information, or how any participants without evaluable follow-up were handled.

There are no reported analysis results to assess for exclusions, protocol deviations, or sensitivity analyses. The registry record also does not state whether interim analyses were planned or conducted. Accordingly, the available information supports identification of the intended endpoint and population but not a full appraisal of analysis conduct.

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: cardiac-ischemia/infarction (2.4%), secondary malignancy-poss rel to cancer tx (2.4%), febrile neutropenia (1.2%), hemorrhage, gi - rectum (1.2%), hemorrhage, gi - upper gi nos (1.2%).

The serious-event summary lists 84 participants at risk and 8 affected in the R-CHOP plus I-131-tositumomab group. A separate summary lists 84 at risk and 84 affected for other adverse events. These are counts of participants, not a comparison between treatment groups. The registry record does not report deaths in this summary.

The listed serious-event terms include cardiac-ischemia/infarction at 2.4%, secondary malignancy possibly related to cancer treatment at 2.4%, febrile neutropenia at 1.2%, gastrointestinal hemorrhage from rectum at 1.2%, upper gastrointestinal hemorrhage at 1.2%, and lung infection with normal ANC or Grade 1-2 neutrophils at 1.2%. The registry labels these as serious adverse-event terms; the listed percentages should be read as reported and not recalculated.

These figures do not establish that study treatment caused an event. The record’s separate secondary outcome concerns Grade 3 through Grade 5 adverse events related to study drug, but its result is not reported in the registry record. General statistical explanation: event counts and percentages depend on the definitions, observation period, and reporting rules used. They do not by themselves describe duration, recurrence, or comparative risk.

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

The record establishes that a completed phase II, single-group study evaluated a combination involving iodine I 131 tositumomab, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in older patients with advanced non-Hodgkin’s lymphoma. It also specifies PFS at 2 years as the primary outcome and gives the general definition of progression, death, and censoring used for that endpoint.

The record does not report the primary PFS percentage or its 95% confidence interval. It therefore does not show the observed primary outcome or how precisely it was estimated. It also does not report the result for the listed secondary outcome about Grade 3 through Grade 5 adverse events related to study drug. An endpoint definition and a completed status are not substitutes for reported outcome estimates.

Even if the primary estimate were available, the single-group design would support a description of outcomes in the treated study population, not a randomized comparison with another treatment. The results would not, by themselves, establish that the regimen caused a particular outcome or determine what would have occurred under a different approach. The absence of a control group also means that the study cannot directly estimate a relative treatment effect against a concurrent comparator.

The adverse-event summaries report counts and selected terms, but do not establish causation or comparative safety. Their interpretation is further limited by the absence of detailed information about observation, event ascertainment, and the full analysis. The sample-size assumptions describe planning illustrations, not observed power or evidence of treatment effect. Overall, the registry record gives useful design and endpoint definitions, but its posted results are insufficient to quantify the primary outcome or support comparative conclusions.

14. Why This Trial Matters Statistically

This trial is statistically instructive because it pairs a clearly named time-to-event endpoint with a single-group design. PFS incorporates both progression and death, and the registry states when follow-up ends for participants who remain alive and progression-free. Those definitions matter: an endpoint estimate depends on what counts as an event, when observation starts, and how incomplete follow-up is represented.

The design also marks an important boundary on interpretation. A single-group study can characterize outcomes in participants who received the regimen, but it does not create a treatment contrast with a concurrent control. That distinction remains important even when enrollment and follow-up are substantial. The registry lists 86 enrolled participants, but does not report the PFS result or the analysis population count, so the record does not permit assessment of the primary estimate or its precision.

The record illustrates why endpoint definitions, analysis populations, and result reporting need to be read together. A named primary measure without an estimate and confidence interval cannot communicate the magnitude or uncertainty of the outcome. Likewise, a list of adverse-event terms is not a causal comparison, and an outcome listed without its result cannot resolve questions about safety.

Finally, planning illustrations should be separated from the actual design and observed findings. The stated planning assumptions use a hypothetical two-arm, equal-allocation framework, whereas the registered study is single-group. Recognizing that distinction prevents planning calculations from being mistaken for observed evidence or actual trial power. The main statistical value of the available record is therefore its description of the study framework and endpoint rules, alongside clear limits on what can be concluded from the results 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 primary limitation for interpreting outcomes is that the registry record does not report the PFS estimate or its 95% confidence interval. It also does not report the primary analysis denominator, the number of PFS events, the number censored, or the amount and completeness of follow-up. Although the analysis population is defined as all eligible patients who started treatment, the count in that population is not reported.

The single-group design has no concurrent comparator, so treatment outcomes cannot be contrasted within the study against another treatment or usual care. The registry lists masking as none and does not report procedures that would address potential influence on outcome assessment. The record describes clinical progression criteria but does not report details of assessment frequency or independent review.

Enrollment is listed as 86, while the adverse-event summaries list 84 at risk. The registry does not explain the relationship between those counts. The safety information does not include a detailed observation period or the complete methods for event ascertainment in the registry record. Deaths are not reported in the adverse-event summary, and the result for the separately listed treatment-related Grade 3 through Grade 5 outcome is not reported.

The registry record does not report a full statistical analysis plan, the rationale for sample size, a multiplicity approach, interim analyses, or sensitivity analyses. It provides planning assumptions for hypothetical sample-size illustrations, but those are not evidence of observed power and do not change the single-group study design. These reporting gaps limit evaluation of outcome precision, missing data, and analysis decisions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: S0433 Iodine I 131 Tositumomab, Rituximab, and Combination Chemotherapy in Treating Older Patients With Stage II, Stage III, or Stage IV Non-Hodgkin's Lymphoma — NCT00107380.
• Registry record last updated 2016-03-07; status last verified 2016-02.
• Results first posted 2014-02-11.
• 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

The registry describes NCT00107380, a completed phase II single-group study sponsored by SWOG Cancer Research Network. Enrollment is listed as 86, with a study start of 2005-11 and primary completion of 2013-11. The population is described as older patients with advanced non-Hodgkin’s lymphoma; the official title specifies age 60 or older and diffuse large B-cell NHL.

The treatment combined iodine I 131 tositumomab with rituximab and chemotherapy agents cyclophosphamide, doxorubicin, vincristine, and prednisone. The primary outcome is PFS at 2 years, measured from registration to progression or death, with censoring at last contact for participants last known alive and progression-free.

The registry record does not report the primary outcome estimate or confidence interval. It lists adverse-event summaries and a secondary treatment-related adverse-event outcome, but does not report the result for that secondary outcome. The single-group design does not provide a randomized comparator.