Study population, data collection, treatment, and follow-up
The study population was comprised of PC patients enrolled in The Clinical Registry at the Department of Oncology in Tampere University Hospital between 2010 and 2013, as well as patient data retrieved from the hospital information system from 2008 and 2009. Patients were identified from the hospital information system with a specific code depicting EBRT for PC. All patients receiving EBRT as a first-line treatment with curative intent, regardless of tumor T-score and pre-existing risk factors, were included. Only patients who met the following criteria were excluded from this five-year patient population: 1) The EBRT ended after December 31, 2013; 2) The patient was not a resident of a municipality belonging to the Pirkanmaa Healthcare District (detailed follow-up data were unavailable); 3) Metastatic disease (M1); 4) Premature cessation of EBRT due to a sudden illness (unrelated to prostate cancer); 5) EBRT as a second-line treatment (failed androgen deprivation monotherapy or salvage radiation therapy after radical prostatectomy); and 6) No radical treatment (palliative radiotherapy).
The final population was comprised of 665 men (Figure 1). The study was approved by the ethical committee of the region, and permission to access patient report inquiries was granted by the director of the faculty of science (ETL R155025). The data collection occurred between May 2015 and March 2019 and included an assessment of the patient demographics, medical history and carcinoma-related details from the patient records of Tampere University and Tampere City Hospital.
Most men received treatment in the form of intensity-modulated radiation therapy (IMRT) with image-guided assistance (N = 646, 97.1 %). The remaining cases were treated with either volumetric-modulated arc therapy (VMAT, N = 7, 1.1 %) or three-dimensional conformal radiotherapy (3D-CRT, N = 12, 1.8 %). Altogether, 367 men (55.1 %) received androgen deprivation therapy (ADT) with a median duration of 20.3 months (range 1.6-127.4, N=). In 9 cases (2.5 %), the duration of hormonal treatment could not be determined due to missing data. Among patients receiving ADT, 283 patients (76.9 %) patients received a combined neoadjuvant-adjuvant –treatment, 74 patients (20.1 %) received only the neoadjuvant and 11 patients (3.0 %) only the adjuvant treatment.
Of patients belonging to a high recurrence risk group (N = 360) in the D’Amico classification (9), 295 men (81.9 %) received ADT. In the intermediate-risk group (N = 183), 62 men (33.8 %) received ADT. The median duration of the medicinal treatment in the high-risk group was 25.0 months (range [2.0−127.4], N = 288), and in the intermediate-risk group, it was 6.0 months (range [1.5−33.7], N=61). In the low-risk group (N = 121), ADT was given to 10 men (8.3 %). One patient could not be classified using the D’Amico system because of the inaccurate T grade documenting. A urologist decided to begin a neoadjuvant or adjuvant medication, based on the risk group and individual factors such as quality of life concerns. The patient had the right to decline from hormonal treatment. The long-term follow-up after EBRT was also mainly carried out by the department of urology and in lower-risk groups partly transferred back to primary healthcare.
ADT used most frequently was luteinizing-hormone-releasing hormone (LHRH) analog monotherapy with either leuprorelin or goserelin (N = 308, 83.9 %). In 46 (12.5 %) cases, this treatment was combined with antiandrogen bicalutamide. Two men (0.54 %) received bicalutamide monotherapy, and 9 men (2.5 %) received an LHRH-agonist (degarelix). Furthermore, two men (0.54 %) participated in the SPCG-13 adjuvant phase III clinical trial and were treated with six cycles of docetaxel combined with a hormonal adjuvant treatment after radiotherapy (10).
The initial diagnosis was performed through a pathological examination of core needle biopsies of the prostate in a vast majority of the cases (N = 656, 98.6 %). In nine cases (1.4 %), cancer was an incidental finding after a routine examination of the surgical pathology slides after transurethral resection of the prostate (TURP). Standardly, a transrectal 12-core biopsy procedure was used, although there were patients with fewer or more biopsy cores (median 12.0, range [2−19], N = 612). The median percent of positive biopsy cores (PPC) was 40.0 % (range 5.9 % − 100 %).
TNM-staging was established using both a pathology report and MRI imaging, through which the physician determined the clinical stage. Bone scans were performed to high-risk patients to exclude metastatic progression. The risk of lymph node and seminal vesicle metastasis was assessed by Memorial Sloan Kettering Cancer Center (MSKCC)-nomogram (11), and the radiation plan was selected accordingly. If the risk of seminal vesicle invasion was over 15 % seminal apices were included in the treatment site and if lymph node involvement risk was over 35 % pelvic lymph nodes were included in the radiation fields. Based on the nomogram, 452 men (67.9 %) received treatment to the prostate gland and the bases of seminal vesicles alone. In 111 men (16.7 %), seminal apices were included, and in 102 men (15.3 %), both seminal apices and pelvic lymph nodes were radiated in addition to the prostate. Prostate and the bases of seminal vesicles were treated with 5 mm marginal. Treatment marginal to the seminal vesicle apices and lymph nodes was 7 mm. Most patients (N = 536, 80.6 %) were treated with conventional fractionation (2 Gy, 5 times a week) with a dose of 78 Gy, which has been the standard of care until the recent introduction of hypofractionated schedules. A total of 32 men (4.8 %) received hypofractionated radiotherapy treatment with fractions between 2.5-3.1 Gy. The detailed characteristics of the disease profiles and treatments are shown in Table 1 and Table 2, respectively.
Patient follow-up data were collected from the medical records of the urological or oncological departments at Tampere University Hospital and the urological department at the Tampere City Hospital. The PSA-levels were obtained from the Fimlab laboratory database used in every public health institution in Pirkanmaa Hospital District. Each patient attended a PSA laboratory control every 6 to 12 months and a doctor’s appointment at least once a year after the finalization of EBRT. If the patient had symptoms that could indicate a relapse, then the controls were taken more often. The dates of death were obtained from the Tampere University hospital patient records, which are directly synchronized with the Finnish Population Information System.
Outcomes and Statistical analysis
The endpoint for biochemical recurrence-free survival (BRFS) was defined as a PSA increase by 2.0 mg/l or more from the lowest accomplished value after EBRT (nadir). The endpoint for metastasis-free survival (MFS) was determined by metastatic lesions shown in imaging. The date of death was used to determine the endpoint for overall survival (OS) and prostate-cancer specific survival (PCSS). The cause of death was determined by examining the patient records before death or by an autopsy report in selected cases.
No routine CT-scans or plain X-rays were used in the follow-up, and patients were only imaged if they had symptoms that could indicate metastatic disease or if they experienced a biochemical failure. For patients who did not reach the primary endpoint, the last registered PSA-value, physical examination (physician’s appointment) or data collection date (whether the patient had died or not) was used to determine the follow-up time. Survival and follow-up times were determined from the date at which PC was diagnosed by a pathologist.
The data were analyzed using SPSS Statistics 23.0 (IBM Corporation, Armonk, NY, USA) statistical analysis software. By using the aforementioned endpoints, we plotted age-adjusted Kaplan-Meyer curves for BRFS, MFS, PCSS, and OS. To study potential prognostic factors, we used Cox proportional hazards regression model (Forward: LR method). The factors included in the analysis were age at the time of diagnosis, Gleason score, PSA-level at diagnosis, T-stage, N-stage, ADT, ECOG-score and Charlson Comorbidity Index (CCI) score. The variables included in final models were chosen based on their significance preliminary models. P-values below 0.05 were considered statistically significant. The frequencies and weights of different Charlson comorbidities are shown in Table 3. CCI points are determined by summing the weights of the patient's comorbidities.
To study the effects of performance status and comorbidity separately, we plotted two distinct models. In the first model, the CCI score was used as a categorical variant. Comorbidity was classified into three categories: no comorbidity (CCI=0), mild to moderate comorbidity (CCI=1-3) and severe comorbidity (CCI= 4 or more). In the second model, ECOG score was used as a categorical variant. Overall performance was classified: normal (ECOG = 0), mild restrictions (symptoms only during strenuous exercise, ECOG =1) and from moderate to severe restrictions (symptomatic during normal daily activities, ECOG = 2 or more). To assess the potential presence of multicollinearity in the models, we calculated variance inflation factors (VIFs). With all VIFs being under 1.4, no significant multicollinearity was found. A one-way ANOVA test was also performed.