Proton Therapy for Low and Intermediate Risk Prostate Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Proton Therapy for Low and Intermediate Risk Prostate Cancer (NCT00693238), a non-randomized na study. The primary outcome is Acute Grade 3 (NCI CTC v4.0) or Higher Treatment-related Toxicity Rate..

2. Clinical Question

The registry summary frames the treatment objective as giving a shorter course of radiation while limiting side effects on normal bladder and rectal tissues, without decreasing the chance of killing prostate cancer cells. That statement describes the study's rationale; it is not itself an outcome result. The registry record does not list a usual-course comparison group, so the design does not directly test the shorter course against the longer course described in the summary.

Disease control is listed as a secondary outcome, but its results are not reported in the registry record. The primary endpoint concerns acute treatment-related toxicity rather than disease control. The record therefore establishes what question the primary outcome was intended to address, but does not provide the primary outcome result or a comparative estimate between these regimens.

3. Trial Design

The study is titled as a phase II investigation of hypofractionated image-guided proton radiation therapy for low- and intermediate-risk adenocarcinoma of the prostate. Although the title identifies it as phase II, the registry's phase field is NA. The registry lists the University of Florida as sponsor, a parallel model, non-randomized allocation, and no masking. Its status is completed. The listed start is 2008-04 and primary completion is 2012-06; enrollment is 228.

The record describes separate low-risk and intermediate-risk proton radiation arms. The low-risk regimen is 70 Gy/CGE in 28 fractions of 2.5 Gy/CGE/fx. The intermediate-risk regimen is 72.5 GY/CGE in 29 fractions of 2.5 Gy/CGE/fx. These are not randomized treatment arms within a shared risk group: the record identifies risk category as part of the arm distinction. Consequently, differences between arm summaries cannot be interpreted as treatment effects without addressing the differences in the groups and the non-random allocation.

The registry summary contrasts the intended shorter course, described as 5 ½ weeks, with a usual longer course described as 8 weeks. The listed arms do not include that usual longer course as a comparator. The record gives no further description of eligibility criteria, recruitment, treatment adherence, or any concurrent control group. Those details are not reported in the registry record.

The primary outcome is acute grade 3 or higher treatment-related toxicity, assessed at 6 months after the end of radiation therapy. Disease control is listed as a secondary outcome. The record lists 2 outcome measures and 0 analyses; numerical results for the primary and secondary outcomes are not reported in the registry record. The registry's enrollment figure should not be treated as evidence that every listed participant contributed data to every outcome.

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.

6. Primary Endpoint

The registry lists the primary outcome as Acute Grade 3 (NCI CTC v4.0) or Higher Treatment-related Toxicity Rate., measured over 6 months after the end of radiation therapy.

The primary endpoint is the number of participants with acute grade 3 or higher treatment-related toxicity, using NCI CTC v4.0, at 6 months after the end of radiation therapy. The endpoint is binary at the participant level: a participant either meets the specified toxicity threshold within the stated timeframe or does not. The registry describes the measure as a number of participants.

Using a defined severity threshold focuses the endpoint on more serious toxicity rather than every symptom or treatment effect. The timeframe also matters: an endpoint assessed by 6 months after radiation is not a measure of all possible longer-term effects. This outcome can describe acute toxicity within the specified period, but it does not by itself measure disease control, quality of life, or the full balance of benefits and harms.

The endpoint definition is present, but its observed result is not reported in the registry record. The serious and other adverse-event figures listed in the record are separate entries and should not be substituted for the primary endpoint. The record does not establish that those entries use the same severity threshold, treatment-relatedness criterion, or timeframe as the primary outcome.

For interpretation, the intended endpoint and the reported data must be distinguished. A prespecified outcome description indicates what investigators intended to count; it does not show how many participants met that definition. Without the primary endpoint result and its analysis details, the frequency and precision of acute grade 3 or higher treatment-related toxicity cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary because it classifies participants according to whether they experienced the defined toxicity threshold during the stated timeframe. For a binary outcome, a natural descriptive summary is the number meeting the definition and the number assessed. A proportion can also be useful, but it requires a clearly stated denominator and an outcome definition that matches the primary endpoint. The registry record supplies the endpoint definition but not its primary result.

For an estimated event proportion, uncertainty is commonly expressed with a confidence interval. In general, a confidence interval describes a range of values compatible with the observed data under the method's assumptions; it is not a guarantee that the true value lies in that range. Interval width reflects both the amount of information and the variability in the data. The primary endpoint's estimate and confidence interval are not reported in the registry record, so its precision cannot be evaluated.

A comparison between groups requires more than separate event counts. Random allocation can support a causal comparison by balancing, on average, factors that affect outcomes, while non-random allocation can leave group differences entangled with treatment differences. Here, the listed arms correspond to low-risk and intermediate-risk disease and use different regimens. The record explicitly identifies the allocation as non-randomized and warns that the arms are not a like-for-like control comparison. A numerical contrast, even if calculated from arm-level summaries, would therefore be descriptive rather than a clean estimate of the causal effect of one regimen versus another.

The record lists participant counts for serious and other adverse events. Those entries should be interpreted according to the category labels and the stated at-risk counts, not assumed to be interchangeable with the primary endpoint. The primary outcome includes a specific grade threshold, treatment-relatedness, and assessment timeframe. The adverse-event entries do not establish that all three criteria were applied identically. General statistical practice requires matching the estimand—the outcome and population a result is meant to describe—to the definition actually used in data collection and analysis.

Multiple outcomes raise a multiplicity question. When several outcomes or comparisons are tested, the chance of a false-positive finding can increase if each is assessed without an appropriate strategy. General approaches can include prespecifying a primary outcome, controlling an overall error rate, or treating secondary findings as exploratory. The registry identifies a primary endpoint and lists disease control as a secondary outcome, but an adjustment strategy, testing hierarchy, and analysis plan are not reported in the registry record. No analyses are listed, so it is not possible to determine how multiplicity was handled in practice.

Missing data affect both the estimated outcome frequency and its uncertainty. If participants are not assessed at the endpoint time, a complete-case result may describe only those with available measurements and can be biased when missingness is related to prognosis or toxicity. Other methods make different assumptions about the unobserved outcomes. The registry record does not report the amount or handling of missing primary-outcome data, the number assessed at the endpoint, or the assumptions used for any missing-data method. These details are not reported in the registry record.

Analysis populations also matter. An intention-to-treat population, a treated population, and a population with evaluable follow-up answer different questions. The record does not specify which population was used for the primary analysis, and no primary analysis is listed. The enrollment figure alone cannot establish who received treatment, completed follow-up, or contributed to each outcome. Those analysis-population details are not reported in the registry record.

The planning assumptions describe illustrations computed from the observed effect, with 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. Such values are prospective planning illustrations, not observed power. They are also not evidence of the original design rationale: a protocol-based sample-size justification is not reported in the registry record. The record's note that all other sample-size summaries give participants per arm is a convention for those planning illustrations, not a statement about actual enrollment or outcome analysis.

Finally, statistical significance and clinical importance are distinct concepts. A small p-value, when available, addresses compatibility with a specified null model under assumptions; it does not by itself establish importance, causation, or applicability. An effect estimate and its uncertainty are needed to assess magnitude and precision. Since the primary result and inferential analysis are not reported in the registry record, neither statistical significance nor the clinical importance of the primary endpoint can be assessed from this 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("Low Risk Proton Radiation", "Intermediate Risk Proton Radiation")
n      <- c(122, 106)
events <- c(0, 0)
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  Low Risk Proton Radiation  122  0  0.0  0.0  3.0  -0.0  3.1  0.0  3.0
ARM  Intermediate Risk Proton Radiation  106  0  0.0  0.0  3.4  0.0  3.5  0.0  3.4

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies acute grade 3 or higher treatment-related toxicity as the primary outcome and lists disease control as a secondary outcome. It does not report a multiplicity strategy, such as an adjustment for testing multiple outcomes or a prespecified sequence for interpreting them. The record lists 2 outcome measures and 0 analyses, so no statistical testing approach can be evaluated. Whether multiplicity was considered in a protocol or analysis plan is not reported in the registry record.

Missingness is also not described. The record does not state how many participants had an assessment at the primary endpoint timeframe, whether any endpoint observations were unavailable, or how missing outcomes were handled. It does not report an analysis population for the primary endpoint. The enrollment figure of 228 does not resolve these issues: enrollment is not the same as the number assessed or analyzed for a specific outcome.

In general, missing outcome data can limit interpretation if the participants with available measurements differ systematically from those without them. The effect depends on why data are missing and on the assumptions used in analysis. Without a description of follow-up completeness and the missing-data approach, readers cannot assess whether the reported safety entries represent all participants eligible for assessment or a subset. No such assessment is possible from the registry record because the relevant information is not reported.

These omissions do not establish that analyses or procedures were absent from the conduct of the study. They mean only that multiplicity, missing-data handling, and analysis-population details are not reported in 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: rectal hemmorhage (grade 3) (0.9%), proctitis (grade 3) (0.9%), urinary retention (grade 3) (0.8%), hematuria (grade 3) (0.8%).

The registry lists serious and other adverse-event entries separately for each risk-specific arm. In the low-risk arm, 2 participants are listed with serious events among 122 at risk, and 26 with other events among 122 at risk. In the intermediate-risk arm, 2 are listed with serious events among 106 at risk, and 21 with other events among 106 at risk. These are reported counts; they should not be combined across arms or treated as a comparative treatment effect.

The listed serious-event terms are Rectal hemmorhage (grade 3) at 0.9%, Proctitis (grade 3) at 0.9%, Urinary retention (grade 3) at 0.8%, and Hematuria (grade 3) at 0.8%. The registry record does not explain the denominator or the relationship between these term-level percentages and the arm-level counts. It also does not clarify whether a participant could be represented under more than one term.

These entries are not necessarily the same as the primary endpoint. That endpoint specifically concerns acute grade 3 or higher treatment-related toxicity by 6 months after the end of radiation therapy. The adverse-event entries do not establish that they share its treatment-relatedness definition or timeframe. They are descriptive safety information, not evidence from a randomized comparison.

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

The record establishes that the study examined hypofractionated image-guided proton radiation in low- and intermediate-risk prostate cancer, with regimens specified separately by risk group. It also identifies acute grade 3 or higher treatment-related toxicity at 6 months after radiation as the primary outcome and disease control as a secondary outcome. These design details clarify what the study set out to describe.

The record does not report the primary endpoint result or a disease-control result. It therefore cannot establish the observed frequency of the primary toxicity outcome, the precision of that frequency, or the size of any difference between regimens. The adverse-event counts and term-level percentages offer descriptive information, but they do not substitute for the primary endpoint or a complete analysis.

The study's non-randomized allocation is central to interpretation. The arms are defined by different risk categories and different radiation schedules, rather than by random assignment of comparable participants to alternative regimens. Any difference between arm summaries could reflect the underlying groups, treatment schedules, or other factors. It should not be interpreted as proof that one schedule caused a better or worse outcome than another.

The registry summary describes an intended shorter course and compares its goal with a usual longer course, but the listed study arms do not include that usual longer course as a control. The record therefore does not provide a direct comparison of the shorter course against the longer course described in the rationale. The treatment objective in the summary should not be mistaken for evidence that the objective was achieved.

More broadly, a completed study designation does not mean that all outcome data or analyses are available in the registry. The listed enrollment and adverse-event entries do not answer every question about eligibility, follow-up, missing data, treatment adherence, or long-term outcomes. Those details are not reported in the registry record. The conclusions that can be drawn should remain limited to the design and descriptive entries that the record actually reports.

14. Why This Trial Matters Statistically

This study illustrates why the design and population behind an arm comparison matter as much as the numerical summaries. The low-risk and intermediate-risk arms are not randomized alternatives for the same population; they correspond to different risk groups and different treatment regimens. Treating their outcomes as though they came from a controlled comparison would confuse prognostic group differences with possible regimen effects. The record itself cautions against a like-for-like interpretation.

It also illustrates the distinction between an endpoint definition and an endpoint result. A registry can state a precise toxicity threshold and timeframe while not reporting the number of participants who met it. Readers need both the outcome definition and the observed data, along with an analysis description, to assess frequency and precision. Here, the primary result and analyses are not reported in the registry record.

The safety entries further demonstrate why outcome labels and denominators must be read carefully. Arm-level serious and other event counts, term-level percentages, and a primary treatment-related toxicity endpoint are not automatically interchangeable. Without detail on definitions, overlap, and denominators, they answer different or incompletely specified questions.

Finally, the study summary's comparison with usual longer-course radiation highlights the difference between a rationale and a trial contrast. The listed arms do not include that comparator. The record can therefore describe the regimens and their associated entries, but it cannot supply a direct controlled comparison with the longer course. These distinctions are essential for interpreting registry data without overstating what the design can establish.

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 main limitation for interpreting results is that the primary endpoint is defined but its result is not reported in the registry record. No primary analysis, estimate, or uncertainty interval is listed. Disease control is named as a secondary outcome, but its result is also not reported. This prevents assessment of the stated primary question and the listed secondary outcome.

The non-randomized design limits causal interpretation. The arms correspond to distinct risk categories and different regimens, so arm-level differences cannot isolate a treatment effect. The record also lacks a usual longer-course comparator, despite describing that course in the study rationale. It does not support a direct comparison between the shorter course and that usual course.

Details needed to judge the safety summaries are incomplete. The record does not specify how the term-level percentages relate to the arm-level event counts, their denominators, or whether participants could contribute to multiple event terms. It does not establish that these entries share the primary endpoint's treatment-relatedness definition and timeframe.

Eligibility criteria, outcome follow-up completeness, missing-data handling, and analysis populations are not reported in the registry record. A statistical analysis plan, multiplicity approach, and protocol-based sample-size justification are also not reported. These gaps limit assessment of bias, precision, and the intended inferential framework. The listed enrollment and completed status do not resolve those uncertainties.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Proton Therapy for Low and Intermediate Risk Prostate Cancer — NCT00693238.
• Registry record last updated 2023-09-18; status last verified 2023-09.
• Results first posted 2013-07-24.
• 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

NCT00693238 is a completed, non-randomized, unmasked, parallel study sponsored by the University of Florida. Its title identifies a phase II study, while the registry phase field is NA. The listed enrollment is 228; the start is 2008-04 and primary completion is 2012-06.

The study describes hypofractionated proton radiation regimens for low- and intermediate-risk prostate cancer. Its primary endpoint is acute grade 3 or higher treatment-related toxicity at 6 months after the end of radiation therapy; disease control is listed as a secondary outcome. The registry lists 2 outcome measures and 0 analyses.

Arm-level serious and other adverse-event counts and several serious-event term percentages are recorded. The primary outcome result, secondary outcome result, analysis details, missing-data approach, and analysis populations are not reported in the registry record. The non-randomized, risk-specific arms should not be read as a like-for-like control comparison.