Objectives
This study aims to describe demographics, clinical characteristics and estimate outcomes of PCa patients under initial conservative management (delayed treatment) across a network of databases in the overall population and subgroups of patients identified by individual disease characteristics, demographics and comorbidities. In detail, the main objectives of the study are:
1. To describe demographic and clinical characteristics of patients with PCa under conservative management (delayed treatment, target cohort 3)
To estimate clinical outcomes of PCa patients under conservative management (delayed treatment):
Overall survival
Cause-specific survival (cancer and other-causes)
Time to symptomatic progression
Time to palliative (or curative) treatment initiation
To characterize detailed treatments patterns and outcomes of patients with PCa under conservative management (delayed treatment) who initiated treatment:
· Distribution of treatment type: curative and palliative
· Distribution treatment categories: ADT, RT, RP, systemic anti-neoplastic treatment
4. To characterize demographics, clinical characteristics and estimate long-term outcomes of patients newly diagnosed with PCa across a network of databases (target cohort 1)
5. To characterize demographics, clinical characteristics and estimate long-term outcomes of patients newly diagnosed with PCa who received immediate treatment (target cohort 2)
6. To characterize demographics, clinical characteristics and estimate long-term outcomes of patients newly diagnosed with PCa who delayed immediate treatment (target cohort 4)
Data Sources
The study will rely on large observational data, namely population-based registries, electronic health records (EHR) and insurance claims data. The data will be analyzed using a federated model, where the data remain with the data custodians and only the analysis results are shared and published.
Case series and AS cohorts will not be considered.
Study design
The study will be an observational cohort study based on routinely collected health care data which has been mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM).
First, cohorts of individuals with PCa will be identified. Patients’ demographics and clinical characteristics at or prior to index date (defined below) and treatments and outcomes of these individuals at or after their index date will be described (clinical characterization).
Target Cohort 1 - Newly Diagnosed PCa: Adult patients with newly diagnosed PCa with at least 365 days of prior observation
· Male adults (age ≥ 18)
· a diagnosis of PCa (Index date: date of first visit with PCa dx)
· a prostate biopsy within 30 days of the first visit with PCa diagnosis
· no history of PCa or prostate dysplasia within 365 days prior to index
· no drug exposure to ADT or androgen agonist/inhibitor within 365 days prior to index
Target Cohort 2 - Immediate management: Adult patients with newly diagnosed PCa and treatment within six months with at least 365 days of prior observation
· Male adults (age ≥ 18)
· a diagnosis of PCa
· a prostate biopsy within 30 days of the first visit with PCa diagnosis
· no history of PCa or prostate dysplasia within 365 days prior to first PCa diagnosis
· no drug exposure to ADT or androgen agonist/inhibitor within 365 days prior to first PCa diagnosis
· receipt of at least one treatment (curative or palliative) within the first six months after PCa diagnosis (Index date: six months after first prostate cancer diagnosis)
Target Cohort 3 - Delayed management: Adult patients with newly diagnosed PCa and no treatment within 6 months of their diagnosis
· Male adults (age ≥ 18)
· a diagnosis of PCa
· a prostate biopsy within 30 days of the first visit with PCa diagnosis
· no history of PCa or prostate dysplasia within 365 days prior to first PCa diagnosis
· No drug exposure to ADT or androgen agonist/inhibitors within 365 days prior to first PCa diagnosis
· No treatment (curative or no palliative) within the first six months of prostate cancer diagnosis (Index date: six months after first prostate cancer diagnosis)
Target Cohort 3.1 – Intermediate- and high-risk PCa watchful waiting: Adult patients with newly diagnosed intermediate- or high-risk PCa who received no treatment within 6 months of their diagnosis
· Male adults (age ≥ 18)
· a diagnosis of PCa
· a prostate biopsy within 30 days of the first visit with prostate cancer diagnosis
· no history of PCa or prostate dysplasia within 365 days prior to first PCa diagnosis
· No drug exposure to ADT or androgen agonist/inhibitors within 365 days prior to first PCa diagnosis
· Intermediate -risk or high-risk PCa according to EAU risk groups [5]
· No curative or palliative treatment within the first six months of PCa diagnosis (Index date: six months after first prostate cancer diagnosis)
Target Cohort 3.2.1 - low-risk PCa watchful waiting (low-risk PCa patient not managed with AS during the first 18 months): Adult patients with newly diagnosed low-risk PCa who received no treatment within the first six months of diagnosis and were not managed with AS in the first 18 months of diagnosis
· Male adults (age ≥ 18)
· a diagnosis of PCa
· a prostate biopsy within 30 days of the first visit with PCa diagnosis
· no history of PCa or prostate dysplasia within 365 days prior to first PCa diagnosis
· No drug exposure to ADT or androgen agonist/inhibitors within 365 days prior to first PCa diagnosis
· No curative or palliative treatment within the first six months after PCa diagnosis
· Low-risk PCa
· No biopsy within the first 18 months after first diagnosis
· <3 PSA testing within the first 18 months after first diagnosis
· <3 urological visits within the first 18 months after diagnosis (Index date: 18 months after first prostate cancer diagnosis)
Target Cohort 3.2.2 - Low-risk PCa AS (low-risk PCa managed with AS during the first 18 months): Adult patients with newly diagnosed low-risk PCa who received no treatment within 6 months and were managed with AS in the first 18 months of diagnosis
· Male adults (age ≥ 18)
· a diagnosis of PCa
· a prostate biopsy within 30 days of the first visit with PCa diagnosis
· no history of PCa or prostate dysplasia within 365 days prior to first PCa diagnosis
· No drug exposure to ADT or androgen agonist/inhibitors within 365 days prior to first PCa diagnosis
· No curative or palliative treatment within the first six months after PCa diagnosis
· Low-risk PCa
· At least one biopsy or ≥3 PSA testing or ≥3 urological visits within the first 18 months after the first diagnosis (Index date: 18 months after prostate cancer diagnosis)
Target Cohort 4 - Delayed management and further treated PCa:
· Male adults (age ≥ 18)
· a diagnosis of PCa
· a prostate biopsy within 30 days of the first visit with PCa diagnosis
· no history of PCa or prostate dysplasia within 365 days prior to first PCa diagnosis
· No drug exposure to ADT or androgen agonist/inhibitors within 365 days prior to first PCa diagnosis
· No curative or palliative treatment within the first six months after PCa diagnosis
· Initiation of curative treatment or Palliative treatment after six months of first prostate cancer diagnosis (Index date: date of treatment initiation)
Target Cohort 4.1 - Delayed curative management and further treated curatively PCa:
· Male adults (age ≥ 18)
· a diagnosis of PCa
· a prostate biopsy within 30 days of the first visit with PCa diagnosis
· no diagnosis or history of PCa or prostate dysplasia within 365 days prior to first PCa diagnosis
· No drug exposure to ADT or androgen agonist/inhibitors within 365 days prior to first PCa diagnosis
· No curative or palliative treatment within the first six months after PCa diagnosis
· Curative treatment (RP, RT or systemic therapies) after six months of first prostate cancer diagnosis (Index date: date of treatment initiation)
Target Cohort 4.2 - Delayed management and further treated palliatively PCa:
· Male adults (age ≥ 18)
· a diagnosis of prostate cancer
· a prostate biopsy within 30 days of the first visit with PCa diagnosis
· no diagnosis or history of PCa or prostate dysplasia within 365 days prior to first PCa diagnosis
· No drug exposure to ADT or androgen agonist/inhibitors within 365 days prior to first PCa diagnosis
· No curative or palliative treatment within the first six months after PCa diagnosis
· Palliative treatment (RT or systemic therapies) after six months of initial prostate cancer diagnosis (Index date: date of treatment initiation)
To include newly diagnosed PCa patients not undergoing biopsy at the time of diagnosis, more inclusive cohorts were defined by including patients with a PSA value above 50 ng/mL within 30 days of PCa diagnosis with or without a PCa biopsy in the study.
Outcome Cohort 1. Death from any causes
Outcome Cohort 2. Symptomatic progression defined as occurrence of any of the following symptoms during the follow-up
· Skeletal-related events (i.e., compression fracture of vertebral column or spinal cord compression)
· Urinary retention
· Hydronephrosis and acute kidney failure
· Bowel occlusion/obstruction
Outcome 3. Treatment (curative or palliative) initiation. Initiation of PCa-related palliative or curative related treatment such as surgery, radiotherapy and systemic anti-neoplastic during the follow up
Curative treatment was defined as having any of the following:
1. Prostatectomy (radical, open, laparoscopic radical and robot assisted radical)
2. Radiotherapy
· low dose brachytherapy
· high dose brachytherapy
· intensity modulated radiotherapy
· external beam radiation therapy (EBRT)
· Cyberknife
· Proton-beam Therapy
3. Focal therapy (HIFU, Cryotherapy, RFA)
Palliative treatment was defined as having any of the following:
Radium 223
Lutetium-117 PSMA therapy
Orchiectomy
Palliative TURP, TUIP
Chemotherapy (Docetaxel, paclitaxel, cabazitaxel, mitoxantrone)
Immunotherapy (sipuleucel-T, pembrolizumab)
PARP inhibitors (olaparib, rucaparib)
Androgen receptor inhibitor (ARTA)
ADT (ATC for GnRH agonists: L02AE OR GnRH antagonists: L02BX OR anti-androgens: L02BB)
Radiotherapy following symptoms
Placement of ureteral stent or nephrostomy for acute kidney failure
Colostomy
Chronic foley catheter placement
Pelviectomy (Total pelvic exenteration)
Suprapubic catheter placement
Outcome Cohort 4. Curative treatment initiation
Outcome Cohort 5. Palliative treatment initiation
Outcome Cohort 6. Hospitalization within 12 months after onset of symptoms
Outcome Cohort 7. ER visits within 12 months after onset of symptoms
Outcome Cohort 8. Cancer-specific mortality: occurrence of death from PCa
Outcome Cohort 9. Other cause mortality: occurrence of death from causes other than PCa
Follow-up
Patients are followed up from index date until death, diagnosis with another malignancy (except for non-melanoma skin cancer), or end of observation period.
Stratifications
Each target cohort will be analyzed in full and stratified on factors based on the following pre-index characteristics, all strata are pending meeting minimum reportable cell counts (as specified by data owners):
- Comorbidities classified according to standardized systems (e.g., Charlson Co-morbidity Index). Patients will be stratified into three groups:
1. CCI=0
2. CCI=1
3. CCI>=2
- Performance status (PS) (e.g., ECOG PS or Karnofsky PS) at index. In case PS is recorded on the Karnofsky scale (KPS), KPS will be converted to ECOG PS using the methodology outlined in Table x
1. ECOG=0
2. ECOG =1
3. ECOG >=2
- Type of comorbidity
1. CVD
2. Obesity
3. Hypertension
4. Concomitant malignancy before PCa diagnosis
5. Total Cardiovascular Disease Event
6. Stroke
7. Type 2 Diabetes
8. VTE
9. Anxiety; psychological distress (before and after diagnosis)
10. Respiratory disease (chronic obstructive pulmonary disease (COPD) or asthma)
- Disease status:
1. localized (T1-2 AND N0 AND (M0 or Mx))
2. locally advanced ((T3-4 OR N1) AND (M0 or Mx))
3. Metastatic (M1)
- Disease characteristics at diagnosis:
1. Clinical stage at the time of diagnosis:
§ cT1
§ cT2
§ cT3-4
2. PSA at diagnosis:
§ <10 ng/mL or ug/L
§ 10-20 ng/mL or ug/L
§ >20 ng/mL or ug/L
3. biopsy Grade group (Gleason score)
§ 1 (3+3)
§ 2 (3+4)
§ 3 (4+3)
§ 4 (4+4 OR 3+5 OR 5+3)
§ 5 (5+5 OR 4+5 OR 5+4)
4. EAU risk group
§ low-risk (PSA <10 ng/ml AND (Gleason score 6 OR grade group 1) AND c1/cT2a),
§ intermediate-risk (PSA 10-20 ng/ml OR (Gleason score 7 OR grade group 2-3) OR cT2b)
§ high-risk (PSA >20 ng/ml OR (Gleason score 8-10 OR grade group 4-5) OR cT3, cT4)
- Age categorized into
1. 5-year groups
2. <55 years, 55-80 years and ≥80 years
- Race/ethnic groups
- Smoking categorized as smokers and non-smokers
- Family history of PCa, breast cancer, ovarian cancer, bowel, or pancreatic cancer or family history of BRCA mutation
- Somatic or germline mutations in BRCA2, BRCA1, ATM, MLH1, MSH1, MSH2, MSH6, CHEK2, RAD51B and PALB2 genes
- Physical therapy/exercise
Features of interest
These features span across the full set of target cohorts and research questions of interest in subgroups. Some features will only be relevant in some target cohorts or some subgroups, but the full list is given here.
Pre-index characteristics
These features will be described as assessed during the year (-1 to -365 days) pre-index:
Demographics:
- Age at diagnosis (median, IQR)
- Year of diagnosis (median, IQR)
- Time to death, symptomatic progression and treatment initiation (median, IQR)
- Race/ethnicity
Concept-based:
- Condition groups (SNOMED + descendants), >=1 occurrence during the interval
- Drug era groups (ATC/RxNorm + descendants), >=1 day during the interval which overlaps with at least 1 drug era
Cohort-based:
- Disease status:
- localized (T1-2 AND N0 AND M0)
- locally advanced (T3-4 OR N1)
- Metastatic (M1)
- Disease characteristics:
- PSA at diagnosis (median, IQR)
- Biopsy grade group (median, IQR)
- clinical stage (cT1, cT2, cT3-4)
- EAU risk group (low, intermediate, high)
- Clinical characteristics/comorbidities:
- CVD
- Obesity
- Hypertension
- Concomitant malignancy before PCa diagnosis
- Total Cardiovascular Disease Event
- Stroke
- Type 2 Diabetes
- VTE
- Anxiety; psychological distress (before and after diagnosis)
- Respiratory disease
- Family history of PCa
- Genetic profile of patient
Post-index characteristics
These features will be described in two different time windows: at index date (day 0) and in the 365 days from index date (0 to 365 days). The characteristics will include:
Concept-based:
- Condition groups (SNOMED + descendants), >=1 occurrence during the interval
- Drug era groups (ATC/RxNorm + descendants), >=1 day during the interval which overlaps with at least 1 drug era
Cohort-based:
● ER visits within 12 months after onset of symptoms
● Hospitalization within 12 months after onset of symptoms
● Death
● PCa death
● Death from other causes
● Treatment initiation
Symptomatic progression
Analysis: Characterizing cohorts
All analyses will be performed using code developed for the OHDSI Methods library. The code for this study can be found at link. A diagnostic package built off the OHDSI Cohort Diagnostics (https://ohdsi.github.io/CohortDiagnostics/) library, is included in the base package as a preliminary step to assess the fitness of use of phenotypes on your database. If a database passes cohort diagnostics, the full study package will be executed. Baseline covariates will be extracted using an optimized SQL extraction script based on principles of the FeatureExtraction package (http://ohdsi.github.io/FeatureExtraction/) to quantify Demographics, Condition Group Eras, and Drug Group Eras Additional cohort-specific covariates will be constructed using OMOP Standard Vocabulary concepts.
At the time of executing Feature Extraction, the package will create a data frame in which individuals’ age and sex will be extracted. Individuals’ medical conditions, procedures, measurements and medications will be summarized 1) over the year prior to their index date (-365—1 day), 32) at index date (0day), and 4) at and over the follow-up time (0+ days). Number and proportion of persons with feature variables during time-at-risk windows will be reported by target cohort and specific stratifications. Standardized mean differences (SMD) will be calculated when comparing characteristics of study cohorts, with plots comparing the mean values of characteristics for each of the characteristics (with the color indicating the absolute value of the standardized difference of the mean).
Baseline disease characteristics at diagnosis will be reported using medians and proportions for non-normally distributed continuous variables and categorical variables, respectively.
The median follow- will be computed for the overall study cohort. The absolute number of patients who experienced overall mortality, cancer-specific mortality, other-cause mortality and disease progression will be reported.
Kaplan-Meier analyses will assess time from PCa diagnosis to overall survival, cancer-specific survival, other-cause-mortality-free survival and symptomatic progression-free survival and time to palliative or curative treatment initiation in the overall cohort and after stratifying patients according to the pre-defined subgroups.
Kaplan-Meier analyses will assess time from disease progression to overall survival, cancer-specific survival and other-cause-mortality-free survival in the overall cohort and after stratifying patients according to the pre-defined subgroups.