PREDYC: Modeling Clinical Failure in Prostate Cancer Patients Based on a Two-stage Statistical Model
Study Details
Study Description
Brief Summary
Biomarker series can indicate disease progression and predict clinical endpoints. When a treatment is prescribed depending on the biomarker, confounding by indication might be introduced if the treatment modifies the marker profile and risk of failure.
The two-stage model fitted within a Bayesian Markov Chain Monte Carlo framework is particularly flexible to account for such data. Prostate-specific antigens in prostate cancer patients treated with external beam radiation therapy can be monitored. In the presence of rising prostate-specific antigens after external beam radiation therapy, salvage hormone therapy can be prescribed to reduce both the prostate-specific antigens concentration and the risk of clinical failure, an illustration of confounding by indication. The prognostic value of hormone therapy and prostate-specific antigens trajectory on the risk of failure based on a two-stage model within a Bayesian framework to assess the role of the prostate-specific antigens profile on clinical failure while accounting for a secondary treatment prescribed by indication. the aim of this research is to model prostate specific antigens using a hierarchical piecewise linear trajectory with a random changepoint. Residual prostate-specific antigens variability can be expressed as a function of prostate-specific antigens concentration. Covariates in the survival model can include : hormone therapy, baseline characteristics, and individual predictions of the prostate-specific antigens nadir and timing and prostate-specific antigens slopes before and after the nadir as provided by the longitudinal process.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Detailed Description
The two-stage modeling approach allows estimation of the regression coefficients in a time-dependent Cox model, while addressing the limitations with the knowledge of the true marker trajectory. In the first stage, the longitudinal process is modeled using a repeated measures component model, such as a random effects model. In the second stage, estimated characteristics of the longitudinal marker trajectory, such as slopes, are included as covariates in a survival model to assess their prognostic value.
Our aim was to highlight the flexibility of a two-stage model fitted within a Bayesian Markov Chain Monte Carlo (MCMC) framework. We applied this model to assess the prognostic value of the prostate-specific antigens (PSA) profile (level and timing of the nadir; pre- and post-nadir slopes) as well as salvage hormonal treatment (HT) on the risk of clinical failure following external beam radiation therapy (EBRT) in the presence of confounding by indication. We first present the longitudinal hierarchical PSA model that we developed earlier. This model was particularly flexible since it allowed us to account for the presence of a random changepoint as well as the modeling of the residual variability as a function of the PSA concentration. We next extend the longitudinal model to a two-stage model by using estimated parameters of the longitudinal process as covariates in a Cox proportional hazards model to assess prognostic factors of clinical failure including baseline characteristics, PSA trajectory, and HT.
Study Design
Outcome Measures
Primary Outcome Measures
- Number of Participants With Clinical Failure After Initiation of Radiotherapy [within 10 years following initiation of radiotherapy]
Clinical failure is defined as any of the following events following initiation of radiotherapy: distant metastases, nodal recurrence, or any palpable or biopsy-detected local recurrence three years after radiation; any local recurrence within three years of RT if the most previous PSA was>2 ng/ml; and death from prostate cancer.
Secondary Outcome Measures
- Number of Participants With Initiation of Salvage Therapy After Radiotherapy [within 10 years following initiation of radiotherapy]
Eligibility Criteria
Criteria
Inclusion Criteria:
-
clinically localized prostate cancer
-
Clinical stage T1 to T4
-
Node and metastasis negative
-
Treated with external beam radiation therapy (RT).
Exclusion Criteria:
- Patients with baseline or planned hormonotherapy
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | INSERM | Bordeaux | France |
Sponsors and Collaborators
- Institut Bergonié
- Institut National de la Santé Et de la Recherche Médicale, France
Investigators
- Principal Investigator: Carine Bellera, PhD, Institut Bergonié
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IB2010-PREDYC
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Patients |
|---|---|
| Arm/Group Description | Eligible Prostate Cancer Patients Undergoing EBRT Treatment |
| Period Title: Overall Study | |
| STARTED | 2384 |
| COMPLETED | 2384 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Eligible Patients |
|---|---|
| Arm/Group Description | Eligible Prostate Cancer Patients Undergoing EBRT Treatment |
| Overall Participants | 2384 |
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
72
(4.7)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
0
0%
|
| Male |
2384
100%
|
| Race and Ethnicity Not Collected (Count of Participants) | |
Outcome Measures
| Title | Number of Participants With Clinical Failure After Initiation of Radiotherapy |
|---|---|
| Description | Clinical failure is defined as any of the following events following initiation of radiotherapy: distant metastases, nodal recurrence, or any palpable or biopsy-detected local recurrence three years after radiation; any local recurrence within three years of RT if the most previous PSA was>2 ng/ml; and death from prostate cancer. |
| Time Frame | within 10 years following initiation of radiotherapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Patients |
|---|---|
| Arm/Group Description | All patients |
| Measure Participants | 2384 |
| Count of Participants [Participants] |
315
13.2%
|
| Title | Number of Participants With Initiation of Salvage Therapy After Radiotherapy |
|---|---|
| Description | |
| Time Frame | within 10 years following initiation of radiotherapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Patients |
|---|---|
| Arm/Group Description | Eligible patients |
| Measure Participants | 2384 |
| Count of Participants [Participants] |
267
11.2%
|
| Title | Prognostic Value of Hormone Therapy on the Risk of Clinical Failure. |
|---|---|
| Description | |
| Time Frame | within 10 years following initiation of radiotherapy |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Patients |
|---|---|
| Arm/Group Description | Eligible patients |
| Measure Participants | 2384 |
| Number (95% Confidence Interval) [hazard ratio] |
0.21
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Patients |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | |
| Comments | ||
| Method | ||
| Comments | ||
| Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
| Estimated Value | 0.21 | |
| Confidence Interval |
(2-Sided) 95% 0.14 to 0.30 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | Two-stage model within a Bayesian framework to assess the role of the prostate-specific antigens profile on clinical failure while accounting for a secondary treatment prescribed by indication. Prostatespecific antigens modeled using a hierarchical piecewise linear trajectory with a random changepoint. Residual prostate-specific antigens variability was expressed as a function of prostate-specific antigens concentration. Covariates in the survival model included hormone therapy, baseline characteristics, and individual predictions of the prostate-specific antigens nadir and timing and prostate-specific antigens slopes before and after the nadir as provided by the longitudinal process. | |
Adverse Events
| Time Frame | up to 10 years following initiation of radiotherapy | |
|---|---|---|
| Adverse Event Reporting Description | This study is a retrospective analysis focussing on the association between the longitudinal PSA trajectory and the time to clinical failure. As such, we did not report on safety. Serious and Other (Not Including Serious) Adverse Events were not monitored/assessed. | |
| Arm/Group Title | All Patients | |
| Arm/Group Description | Eligible patients | |
All Cause Mortality |
||
| All Patients | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/2384 (0%) | |
Serious Adverse Events |
||
| All Patients | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/0 (NaN) | |
Other (Not Including Serious) Adverse Events |
||
| All Patients | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/0 (NaN) | |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr Carine Bellera |
|---|---|
| Organization | Institut Bergonié |
| Phone | 33 0 5 56 33 04 95 |
| c.bellera@bordeaux.unicancer.fr |
- IB2010-PREDYC