Abstract
Background
Potentially curative therapeutic interventions in elderly men with prostate cancer remain controversial due to the presence of concomitant medical comorbidities and concerns of over-treatment and poor tolerance. The purpose of this study is to evaluate long-term outcomes and explore whether comorbidities at presentation may serve to guide patient selection.
Methods
268 consecutive men > = 75 years underwent LDR brachytherapy (BT). Post-implant dosimetry was based on day 0 CT evaluation. EBRT & ADT were delivered to 63.1% & 41.0%, respectively. Biochemical failure (BF) was defined as a PSA > 0.40ng/ml after nadir. Patients with metastatic prostate cancer or non-metastatic castrate resistant disease who died of any cause were classified as dead of prostate cancer. All other deaths were attributed to the immediate cause of death. Multiple parameters were evaluated for impact on survival.
Results
The median patient age was 76.0 years with 67.9% presenting with unfavorable intermediate (UIR) or high risk (HR) disease. The median follow-up was 8.8 years. At presentation, 35.6% presented with 0–1 comorbidities, 24.9% had mid-high normal serum testosterone & 38.4% were never smokers. Overall,10-year BF, prostate cancer specific mortality (PCSM) & overall mortality (OM) were 4.2%, 0.8% & 44.8%. The median post-treatment PSA in biochemically controlled patients was < 0.01ng/ml. 190 patients died with 2 (1.1%) dead of prostate cancer. Death from cardiovascular disease (44.2%) & non-prostate cancer deaths (23.1%) predominated. In Fine-Gray analysis, OM was best predicted by the number of comorbidities with the strongest relationship in those with > = 3 comorbidities (HR 3.36, p < 0.001). No patient required therapeutic intervention for hematuria or hematochezia or developed a rectal fistula. 2 patients developed urinary incontinence.
Conclusions
Definitive treatment is warranted in appropriately selected elderly men with clinically localized prostate cancer. Patient selection criteria to include the number of comorbidities must be assessed to maximize oncologic outcomes and minimize over-treatment. Men with clinically higher risk prostate cancer and no comorbidities are most likely to benefit from definitive treatment regimens.
Keywords: Prostate cancer, Age, Geriatric oncology, Mortality, Brachytherapy, Cardiovascular disease
Background
Because of the long natural history of prostate cancer, potentially curative therapeutic interventions in men > = 75 years of age remain controversial due to the presumed presence of multiple concomitant medical comorbidities which may lead to over-treatment along with concerns regarding quality of life & poor tolerance. While clinicians commonly over-emphasize chronologic age with resultant underestimation of life expectancy, prostate cancer remains the second leading cause of cancer death in men > = 80 years and more than half of all prostate cancer deaths occur in men in their 80’s [1, 2]. These findings are due to the fact that elderly men are more likely to be diagnosed with aggressive prostate cancers. Despite this, advanced age is associated with lower rates of definitive treatment and a greater reliance on androgen deprivation therapy (ADT). In clinically localized prostate cancer, ADT does not improve overall survival and may decrease survival due to an increased risk of major cardiac events [3]. In contrast, a reduction in prostate cancer specific mortality (PCSM) has been reported in higher-risk elderly patients in Europe, the United States and Australia who received definitive local treatment +/- ADT [4–6]. Regardless of age, treatment must be individualized to correspond with the specific needs of each patient. The International Society of Geriatric Oncology (SIOG) recommends the management of older men with prostate cancer be based on their individualized health status, not chronologic age [7].
In 2008, our group reported a relatively small cohort (145 patients) of men > = 75 years of age with promising cancer control. With a median follow-up of 5.8 years, biochemical failure (BF), PCSM & overall mortality (OM) were 2.9%, 0.7% & 35.5%, respectively [8]. In multivariate analysis, BF was best predicted by percent positive biopsies, while OM and non-prostate cancer deaths were best predicted by tobacco. In this study with a greater number of patients and mature follow-up, we will evaluate long-term survival outcomes (including BF, PCSM and OM) and explore whether comorbidities at presentation can predict long-term overall survival.
Methods
From April 1995 through November 2018, 268 consecutive patients > = 75 years of age underwent low-dose rate brachytherapy by a single physician (GM) at the Schiffler Cancer Center in Wheeling, WV. Brachytherapy consists of the transperineal placement of radioactive sources in both intra- and extra- prostatic locations including the proximal seminal vesicles using transrectal ultrasound guidance. Concurrently, treatment planning computers calculate radiation dose distributions. Patients were clinically staged using medical history, physical examination including digital rectal examination, serum PSA, quality of life instruments and post-void residual (PVR) urine. Bone scans and computed tomography of the abdomen/pelvis were obtained at the discretion of the treating or referring physician. All pathology slides underwent review by a pathologist with an expertise in prostate pathology. Beginning in 2002, serum testosterone determinations were added to the pre-treatment and post-treatment evaluations. 165 patients had a testosterone assessment prior to initiation of treatment. Testosterone was assessed by 19 different assays. Each testosterone value was converted to a z-score based on the norm value. The lowest group (low and lower third normal) was determined to be those z-scores that were <−0.66. Risk groups were assigned as per NCCN guidelines (Version 3.2024) [9]. All patients signed an IRB-approved consent form at the time of treatment, which included consent for their clinical data to be used in future research. The consent form detailed the goals and risks of potentially curative treatment, outlined alternative approaches and emphasized that participation in clinical research was voluntary and could be withdrawn at any time. This retrospective study meets all ethical, scientific and administrative standards mandated by our IRB for research involving human subjects. The study was conducted with IRB approval (F24-2).
The brachytherapy planning target volume consisted of the prostate gland with 5 mm peri-prostatic margins except posteriorly (no margin) and the proximal 1.0 cm of the seminal vesicles [10]. This resulted in a planning target volume approximately 1.9 times the actual prostate volume. All post-implant dosimetric calculations were based on day 0 CT evaluation. Prior to 2000, a preplanned approach was utilized. After that date, the preplan served as a template for intraoperative dosimetry with the goal to obtain a post-implant day 0 target volume D90 of approximately 120% and a mean urethral dose of about 110% of prescription. Implant boost doses were 90 Gy for Pd-103 and 110 Gy for I-125. For monotherapy, doses were 125 Gy and 145 Gy for Pd-103 and I-125, respectively. All brachytherapy was performed by a single brachytherapist (GSM).
Supplemental external beam radiation therapy (EBRT, 44–50.4 Gy in 1.8–2.0 Gy fractions depending on clinical and pathologic presentation) was administered prior to brachytherapy boost. The EBRT target volume consisted of the prostate gland and the seminal vesicles with margin. The pelvic lymph nodes were included in higher risk patients. From 1995 to 2005, 3-D conformal techniques were used with subsequent conversion to IMRT. Patients underwent a brachytherapy boost 4 to 15 days following completion of EBRT.
When prescribed, ADT was initiated three months prior to brachytherapy and consisted of either a luteinizing hormone-releasing hormone (LHRH) agonist with an antiandrogen or an LHRH antagonist. ADT was prescribed for marked prostate enlargement and/or adverse pathologic features such as higher Gleason score, PSA or clinical stage. Median ADT duration was 4 months and 12 months in the < = 6 month and > 6 month duration cohorts (maximum duration 36 months).
Patients were monitored by physical examination, including digital rectal examination and serum PSA and testosterone determinations at 3 and 6 month intervals. Primary outcome measures were BF, PCSM and OM. Biochemical failure was defined as a PSA > 0.40 ng/ml after nadir and by the Phoenix definition (nadir PSA + 2). Patients with metastatic prostate cancer or hormone refractory disease without obvious metastases who died of any cause were classified as dead of prostate cancer. All other deaths were attributed to the immediate cause of death. All 268 patients and/or their families were contacted at least every 6 months until death. Cause of death was determined by review of departmental, hospital and primary care records along with death certificates. Differences in cause of death were stratified by risk group.
Clinical, treatment and dosimetric values were presented as continuous or categorical variables. When the data was continuous, patients who died within 4 years of brachytherapy and those who were alive at least 14 years following brachytherapy were compared using an independent t-test. When the data was categorical, and when all cells of the contingency table had at least five entries a Pearson Chi Square was used. When at least one cell contained less than 5 entries a Fisher’s Exact test was utilized. Cardiovascular-related mortality and biochemical failure across the 4 NCCN risk groups were compared using competing risk analysis. Overall mortality was compared across specific groupings of cardiovascular (CVD), ADT, tobacco, pre-treatment testosterone, and the number of comorbidities using Cox regression analysis and displayed graphically using Kaplan-Meier analysis. Univariate analyses were used to determine the hazard ratios of select variables with OM. Variables with p-values < 0.10 were entered into a multivariate analysis. Univariate analyses were used to determine the subdistribution hazard ratios of select variables with OM. Variables that provided p-values < 0.10 were then entered into a multivariate analysis. Univariate analyses were used to determine the subdistribution hazard ratios of select variables with BF. Variables that provided p-values < 0.10 were then entered into a multivariate analysis. A Cox regression was used to determine if the sum of comorbidities (hypertension, hypercholesteremia, cardiovascular disease, diabetes mellitus, unhealthy BMI and tobacco) had an effect on OM. Tobacco was considered a comorbidity if the patient was a current or former smoker. BMI-risk has been determined to be different for older versus younger individuals [11]. A BMI > = 35 was considered to be a comorbidity for those who had never smoked and a BMI < 22.5 or > 27.5 was considered a comorbidity for those who had ever smoked. Univariate and multivariate analyses used a Fine-Gray model to determine subdistribution hazard ratios of select variables for BF. STATA version 18.0 software (StataCorp, College Station, Tx) and SPSS version 29.0 (Chicago, Il) were used for analyses with significance set at p < 0.05.
Results
Table 1. summarizes the clinical, treatment and dosimetric parameters of the 268 patients (median age 76.0 years, range 75–83 with 15 > = 80), stratified by risk group. As expected, there were statistically significant differences in clinical and treatment presentation between risk groups but no clinically significant differences in post-implant dosimetry or comorbidities at presentation. Although when grouped by total comorbidities of 0, 1, 2 and 3+, low risk (LR) patients were more likely to present with fewer comorbid conditions (p = 0.036). 35.6% of all patients presented with 0–1 comorbidities, 24.9% with mid to high normal testosterone and 38.4% were never smokers. The median follow-up for the entire cohort was 8.8 years (range 0.02–22.4 years) with a low of 7.0 years for high risk (HR) and a maximum of 11.0 years for LR patients. 182 patients (67.9%) presented with unfavorable intermediate (UIR) or HR disease. For all patients, the median day 0 D90 was 119.7% of prescription. 242 patients (90.3%) were implanted with Pd-103. Supplemental external beam radiation therapy (EBRT) was administered to 63.1% of patients with only 1 LR patient receiving such treatment. ADT was administered to 41% of patients. 55 patients (20.5%) received < = 6 months of ADT (median 4 months) while 55 patients (20.5%) received > 6 months ADT (median 12 months, maximum 36 months). Longer ADT regimens were primarily restricted to UIR & HR patients. For all biochemically controlled patients, the median post-treatment PSA was < 0.01ng/ml.
Table 1.
Clinical, treatment and dosimetric parameters, of patient > 75 years of age, stratified by risk
| Variable |
Low Risk
n = 44 |
Favorable Intermediate Risk
n = 42 |
Unfavorable Intermediate Risk
n = 103 |
High Risk
n = 79 |
All Patients
n = 268 |
||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Mean (SD) | Med. | Mean (SD) | Med. | Mean (SD) | Med. | Mean (SD) | Med. | p a | Mean (SD) | Med. | |
| Age (yrs) | 76.7 (1.7) | 76.0 | 76.3 (1.3) | 76.0 | 76.3 (1.5) | 76.0 | 76.9 (1.9) | 76.0 | 0.057 | 76.6 (1.6) | 76.0 |
| Follow-up (yrs) | 10.2 (5.1) | 11.0 | 8.5 (4.8) | 8.5 | 9.6 (5.0) | 9.5 | 7.8 (4.6) | 7.0 | 0.026 | 9.0 (4.9) | 8.8 |
| Pretreatment PSA (ng/m2) | 6.8 (1.8) | 6.8 | 7.7 (2.7) | 7.3 | 8.3 (3.7) | 7.2 | 11.7 (8.8) | 8.0 | < 0.001 | 9.0 (5.7) | 7.2 |
| Prostate vol. (cm3) | 34.1 (7.8) | 33.0 | 34.1 (10.6) | 33.2 | 31.6 (9.7) | 30.4 | 26.3 (8.9) | 25.0 | < 0.001 | 30.8 (9.8) | 30.3 |
| Body mass index** | 25.5 (3.1) | 25.7 | 27.2 (3.2) | 26.8 | 27.1 (3.8) | 26.5 | 27.8 (3.8) | 27.3 | 0.010 | 27.1 (3.7) | 26.6 |
| Percent positive biopsy | 25.0 (14.5) | 18.3 | 23.8 (11.6) | 25.0 | 46.2 (21.8) | 50.0 | 51.3 (27.0) | 46.4 | < 0.001 | 40.6 (24.1) | 36.2 |
| Average urethral dose (%) | 115.5 (14.0) | 116.2 | 108.8 (11.5) | 108.8 | 112.7 (13.5) | 111.9 | 115.6 (16.6) | 116.9 | 0.076 | 113.5 (14.4) | 113.1 |
| V100 (%vol) | 96.6 (4.1) | 98.1 | 96.4 (2.7) | 97.2 | 96.8 (3.8) | 98.2 | 97.2 (3.6) | 98.1 | 0.649 | 96.8 (3.6) | 97.9 |
| V150 (%vol) | 67.2 (12.1) | 67.4 | 67.0 (7.2) | 66.5 | 69.2 (12.0) | 72.0 | 71.8 (11.5) | 73.9 | 0.073 | 69.3 (11.3) | 71.1 |
| V200 (%vol) | 35.7 (12.1) | 34.8 | 37.3 (7.1) | 37.2 | 40.1 (10.7) | 42.1 | 43.5 (10.5) | 45.3 | < 0.001 | 39.9 (10.7) | 40.3 |
| D90 (% prescribed dose) | 119.7 (12.7) | 119.5 | 115.1 (8.2) | 113.2 | 119.3 (11.6) | 120.9 | 122.1 (12.7) | 122.6 | 0.024 | 119.5 (11.8) | 119.7 |
| Most recent PSA (ng/m2)* | 0.01 (0.03) | < 0.01 | 0.01 (0.03) | < 0.01 | 0.02 (0.09) | < 0.01 | 0.01 (0.05) | < 0.01 | 0.512 | 0.02 (0.06) | < 0.01 |
| Count | (%) | Count | (%) | Count | (%) | Count | (%) | p x | Count | (%) | |
| C-stage T1b-T2a | 44 | (100) | 42 | (100) | 88 | (85.4) | 60 | (75.9) | < 0.001f | 234 | (87.3) |
| T2b-T2c | 0 | (0) | 0 | (0) | 15 | (14.6) | 18 | (22.8) | 33 | (12.3) | |
| T3c | 0 | (0) | 0 | (0) | 0 | (0) | 1 | (1.3) | 1 | (0.40) | |
| Gleason Group 1 | 44 | (100) | 10 | (23.8) | 2 | (1.9) | 3 | (3.8) | < 0.001f | 59 | (22.0) |
| 2 | 0 | (0) | 32 | (76.2) | 38 | (36.9) | 2 | (2.5) | 72 | (26.9) | |
| 3 | 0 | (0) | 0 | (0) | 63 | (61.2) | 3 | (3.8) | 66 | (24.6) | |
| 4 | 0 | (0) | 0 | (0) | 0 | (0) | 41 | (51.9) | 41 | (15.3) | |
| 5 | 0 | (0) | 0 | (0) | 0 | (0) | 30 | (38.0) | 30 | (11.2) | |
| ADT duration 0 | 30 | (68.2) | 33 | (78.6) | 68 | (66.0) | 27 | (34.2) | < 0.001f | 158 | (59.0) |
| < 6 mons. | 13 | (29.5) | 8 | (19.0) | 23 | (22.3) | 11 | (13.9) | 55 | (20.5) | |
| > 6 mons. | 1 | (2.3) | 1 | (2.4) | 12 | (11.7) | 41 | (51.9) | 55 | (20.5) | |
| Isotope Pd-103 | 29 | (65.9) | 41 | (97.6) | 96 | (93.2) | 76 | (96.2) | < 0.001f | 242 | (90.3) |
| I-125 | 15 | (341.) | 1 | (2.4) | 7 | (6.8) | 3 | (3.8) | 26 | (9.7) | |
| EBRT yes | 1 | (2.3) | 24 | (57.1) | 69 | (67.0) | 75 | (94.9) | < 0.001 | 169 | (63.1) |
| Hypertension yes | 23 | (52.3) | 27 | (64.3) | 60 | (58.3) | 41 | (51.9) | 0.540 | 151 | (56.3) |
| Diabetes yes | 4 | (9.1) | 6 | (14.3) | 11 | (10.7) | 10 | (12.7) | 0.864 | 31 | (11.6) |
| Cardiovascular disease yes | 9 | (20.5) | 11 | (26.2) | 28 | (27.2) | 28 | (35.4) | 0.324 | 76 | (28.4) |
| Hypercholesterolemia yes | 10 | (22.7) | 19 | (45.2) | 38 | (36.9) | 30 | (38.0) | 0.167 | 97 | (36.2) |
| Tobacco use never | 23 | (52.3) | 17 | (40.5) | 30 | (29.1) | 33 | (41.8) | 0.077f | 103 | (38.4) |
| former | 21 | (47.7) | 21 | (50.0) | 66 | (64.1) | 43 | (54.4) | 151 | (56.3) | |
| current | 0 | (0) | 4 | (9.5) | 7 | (6.8) | 3 | (3.8) | 14 | (5.2) | |
| Testosteronet low | 3 | (13.0) | 6 | (22.2) | 15 | (25.9) | 14 | (24.6) | 0.816f | 38 | (23.0) |
| lower 1/3 norm | 16 | (69.6) | 13 | (48.2) | 29 | (50.0) | 28 | (49.1) | 86 | (52.1) | |
| middle 1/3 norm to high | 4 | (17.4) | 6 | (29.6) | 14 | (24.1) | 15 | (26.4) | 41 | (24.9) | |
| Perinueral invasion yes | 2 | (4.5) | 10 | (23.8) | 43 | (41.7) | 41 | (51.9) | < 0.001f | 96 | (35.8) |
| Sum of comorbidities 0 | 10 | (22.7) | 2 | (4.8) | 6 | (5.8) | 10 | (12.7) | 0.051 | 28 | (12.5) |
| 1 | 10 | (22.7) | 8 | (19.1) | 23 | (22.3) | 21 | (26.6) | 62 | (23.1) | |
| 2 | 10 | (22.7) | 15 | (35.7) | 28 | (27.2) | 13 | (16.5) | 66 | (24.6) | |
| 3+ | 14 | (31.8) | 17 | (40.5) | 46 | (44.7) | 35 | (44.3) | 112 | (41.8) | |
For the entire cohort, 10-year BF (PSA > 0.40 ng/ml), PCSM and OM were 4.2%, 0.8% and 44.8% (with a OM of 76.7% at 15 years), respectively (Fig. 1). Ten-year BF was 3.5% for the Phoenix definition. When stratified by risk group, significant differences at 10 years were noted with biochemical failure rates of 0.0%, 2.6%, 3.0% and 9.0% for LR, favorable intermediate (FIR), UIR and HR patients (p < 0.001). OM was not related to risk group (p = 0.804). OM was related to cardiovascular disease (Fig. 2a, p = 0.005), tobacco use (Fig. 2b, p = 0.021) and the number of comorbidities (Fig. 2c, p = 0.002). The use of ADT adversely affected survival in patients with multiple comorbidities (Fig. 2d, p = 0.007) and those with CVD (Fig. 2e, p = 0.037). Patients presenting with testosterone in the low to low-normal range had a higher incidence of OM at 15 years when compared to those with mid-norm to high testosterone (87.5% vs. 71.1%, p = 0.002).
Fig. 1.
Overall mortality, prostate cancer-specific mortality, biochemical failure (post-implant PSA > 0.40) and Phoenix failure (post-implant PSA nadir + 2)
Fig. 2.
a Overall mortality, stratified by cardiovascular disease with 10- and 15- year mortality. b Overall mortality, stratified by tobacco use with 10- and 15- year mortality. c Overall mortality, stratified by the number of comorbidities, with 10- and 15- year mortality. d Overall mortality for those who had ADT, stratified by the number of comorbidities, with 10- and 15- year mortality. e Overall mortality of patients who had CVD and had ADT vs those who did not have CVD and did not have ADT, with 10- and 15- year mortality
Table 2 summarizes causes of death, stratified by risk group. 190 patients died. 2 patients (1.1%) died of prostate cancer with both presenting with HR disease. 84 patients (44.2%) died of cardiovascular disease and 44 (23.1%) died of other cancers. 3 patients (1.6%) died of bladder cancer and 2 (1.1%) died of colon cancer. There were no rectal cancer deaths.
Table 2.
Causes of death, stratified by risk
| Causes of death | LR (%) | FIR (%) | UIR (%) | HR (%) | Total | (%) |
|---|---|---|---|---|---|---|
| Prostate cancer | 0 (0) | 0 (0) | 0 (0) | 2 (4.3) | 2 | (1.1) |
| Lung cancer | 2 (5.4) | 0 (0) | 8 (10.4) | 3 (6.4) | 13 | (6.8) |
| Leukemias and lymphomas | 2 (5.4) | 2 (6.9) | 3 (3.9) | 1 (2.1) | 8 | (4.2) |
| Esophageal and stomach cancer | 4 (10.8) | 1 (3.5) | 1 (1.3) | 2 (4.3) | 8 | (4.2) |
| Bladder cancer | 0 (0) | 1 (3.5) | 0 (0) | 2 (4.3) | 3 | (1.6) |
| Colon cancer | 0 (0) | 1 (3.5) | 0 (0) | 1 (2.1) | 2 | (1.1) |
| Rectal cancer | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 | (0) |
| Other cancer-related causes | 1 (2.7) | 5 (17.2) | 2 (2.6) | 2 (4.3) | 10 | (5.3) |
| Cardiovascular | 15 (40.5) | 10 (34.5) | 33 (42.9) | 26 (55.3) | 84 | (44.2) |
| Pneumonia | 3 (8.1) | 1 (3.5) | 5 (6.5) | 4 (8.5) | 13 | (6.8) |
| COPD | 0 (0) | 1 (3.5) | 5 (6.5) | 0 (0) | 6 | (3.2) |
| Alzheimer’s | 6 (16.2) | 2 (6.9) | 5 (6.5) | 1 (2.1) | 14 | (7.4) |
| Renal failure | 1 (2.7) | 2 (6.9) | 3 (3.9) | 0 (0) | 6 | (3.2) |
| Sepsis | 1 (2.7) | 1 (3.5) | 6 (7.8) | 1 (2.1) | 9 | (4.7) |
| Other non-cancer causes | 2 (5.4) | 2 (6.9) | 6 (7.8) | 2 (4.3) | 12 | (6.3) |
Patients who died within 4 years of brachytherapy (n = 35) were compared to those who lived at least 14 years (n = 45) following treatment to determine if there were discernible differences in presentation that could guide treatment decisions. There were no significant differences in age (77.0 versus 76.0 years, p = 0.058) or individual comorbidities (hypertension, hypercholesterolemia, CVD, diabetes mellitus, unhealthy BMI and tobacco). However, those who lived at least 14 years presented with statistically significant higher serum testosterone levels (p = 0.015) and statistically fewer comorbidities (p < 0.001). 56.8% of long term survivors presented with 0–1 comorbidities and 14.0% with 3 or more comorbidities while 34.2% and 37.1% of those who died within 4 years presented with 0–1 and > = 3 comorbidities. 14-year OM for the entire cohort was 71.7%. The 14-year OM for patients with 0, 1, 2 and > = 3 comorbidities were 31.3%, 66.4%, 86.9% and 74.9% (Table 3, p < 0.001).
Table 3.
Overall mortality at 14 years, stratified by the number of comorbidities
| Number of Comorbidities | Mortality rate at 14 years |
|---|---|
| 0 | 0.313 |
| 1 | 0.664 |
| 2 | 0.869 |
| > 3 | 0.749 |
Because there were no BFs among the 44 LR patients and the natural history of FIR is comparable to LR, the 2 cohorts were combined. In Fine-Gray analysis, BF was most closely related to high risk disease (sHR 8.23; CI 1.04–64.14; p = 0.046) (Table 4.). Analysis to predict PCSM was not feasible due to only 2 prostate cancer deaths (both in HR patients).
Table 4.
Univariate and multivariate analyses for (A) overall mortality and (B) biochemical failure
| A. Overall Mortality | ||||||
| Variable | HR | (95% CI) | p | HR | (95% CI) | p |
| Age | 1.08 | (0.98–1.18) | 0.123 | |||
| PSA | 1.00 | (0.97–1.02) | 0.794 | |||
| Risk (baseline, favorable intermediate & low risk) | 0.785 | |||||
| unfavorable intermediate risk | 0.94 | (0.68–1.31) | 0.706 | |||
| high risk | 1.07 | (0.73–1.56) | 0.733 | |||
| Percent positive biopsy | 1.00 | (0.99–1.01) | 0.679 | |||
| Perineural invasion (no vs. yes) | 1.14 | (0.84–1.54) | 0.413 | |||
| %D90 | 1.01 | (0.99–1.12) | 0.114 | |||
| EBRT (no vs. yes) | 0.94 | (0.71–1.26) | 0.694 | |||
| ADT (no vs. yes) | 1.14 | (0.85–1.52) | 0.397 | |||
| Sum of comorbiditiesc (baseline, 0) | < 0.001 | |||||
| 1 | 2.35 | (1.23–4.49) | 0.010 | 2.35 | (1.23–4.49) | 0.010 |
| 2 | 3.11 | (1.63–5.95) | 0.001 | 3.11 | (1.63–5.95) | 0.001 |
| ≥ 3 | 3.36 | (1.80–6.25) | < 0.001 | 3.36 | (1.80–6.25) | < 0.001 |
| B. Biochemical Failure | ||||||
| Variable | SHR | (95% CI) | p | SHR | (95% CI) | p |
| Age | 1.18 | (0.90–1.55) | 0.233 | |||
| PSA | 1.00 | (0.93–1.07) | 0.934 | |||
| Risk (baseline, low & favorable intermediate low) | 0.052 | |||||
| unfavorable intermediate risk | 2.54 | (0.27–24.15) | 0.419 | 2.54 | (0.27–24.15) | 0.419 |
| high risk | 8.23 | (1.04–65.15) | 0.046 | 8.23 | (1.04–65.15) | 0.046 |
| Percent positive biopsy | 1.02 | (0.99–1.04) | 0.102 | |||
| Perineural invasion (no vs. yes) | 2.11 | (0.65–6.89) | 0.217 | |||
| %D90 | 1.00 | (0.95–1.06) | 0.867 | |||
| EBRT (no vs. yes) | 1.62 | (0.44–5.98) | 0.470 | |||
| ADT (no vs. yes) | 0.51 | (0.14–1.92) | 0.323 | |||
| Sum of comorbiditiesc (baseline, 0) | 0.375 | |||||
| 1 | 2.29 | (0.27–19.69) | 0.447 | |||
| 2 | 0.84 | (0.08–9.06) | 0.889 | |||
| ≥ 3 | 0.72 | (0.08–6.77) | 0.771 | |||
cCardiovascular disease, hypertension, diabetes mellitus, hypercholesterolemia, BMI, and tobaccouse
OM was most closely related to the total number of comorbidities. The relationship was strongest for those patients with 3 or more comorbidities (HR 3.36; CI:1.80–6.25; p < 0.001). One (HR 2.35; CI:1.23–4.79, p = 0.010) and 2 comorbidities (HR 3.11; CI:1.63–5.95; p = 0.001) also were associated with OM.
No patient required therapeutic intervention for hematuria or hematochezia. 2 patients developed GU grade 3 complications (1 patient underwent a post-implant TURP with resultant incontinence and the other underwent a pre-implant TURP and developed gravity incontinence). No patient developed a rectal fistula. In addition, 1 patient died 8 days after brachytherapy of an upper GI bleed and another died 5 weeks after treatment from a myocardial infarction.
Discussion
In this study of 268 men 75 years of age or older treated with LDR brachytherapy for localized prostate cancer, we observed excellent long-term outcomes, including a 10-year BF rate of 4.2% and PCSM of 0.8%. Importantly, overall mortality was strongly predicted by the number of baseline comorbidities was significantly higher OM in patients with > = 3 comorbidities (HR 3.36, p < 0.001). The clinical significance of these findings is that definitive treatment can offer durable cancer control in appropriately selected older men, especially those with limited comorbidities. These results support incorporating comorbidity assessment in the treatment decision-making to better balance the benefits of therapy with overall life expectancy.
Despite continued concerns of over-treatment and poor tolerance of therapeutic interventions, our study supplements the growing body of data supporting definitive treatment in older men with higher risk disease. Kim et al. reported men > = 75 years did as well as younger men in all aspects except for greater OM [12]. They reported a 7-year OS of 68.6%, which is consistent with our current study. Prostate cancer deaths are a significant cause of death in the elderly. Prostate cancer is the second leading cause of cancer death in men > = 80 years of age and more than half of all prostate cancer deaths occur in men in their 80’s [1, 2]. Unfortunately, advanced age is associated with lower rates of definitive treatment. Long-term patient survival following treatment was documented in our series and supports definitive treatment in appropriately selected patients. The efficacy of definitive treatment in elderly patients with clinically localized prostate cancer has been documented by a reduction in PCSM [4–6]. To further evaluate the utility of definitive treatment in men > = 75 years of age with high-risk prostate cancer, the Scandinavian Prostate Cancer Group and the Norwegian Get-Randomized Initiative have initiated a randomized controlled trial comparing curative therapy with conservative approaches [13].
In our series, high rates of biochemical control with undetectable median post-treatment PSA (< 0.01 ng/ml) was noted for all risk groups. In the present era, treatment would be restricted to the 67.9% of patients who presented with UIR or HR. Patients with LR or FIR would be enrolled on active surveillance or watchful waiting protocols. Only 2 prostate cancer deaths occurred and both were in high-risk patients. The limiting factor in our series was overall mortality- 44.8% at 10 years and 76.7% at 15 years. Although it’s conceivable that the high incidence of non-prostate cancer deaths masked BF and PCSM, the overall median follow up of 8.8 years allowed for the vast majority of biochemical failures to manifest themselves, while competing deaths could have under-estimated PCSM to a small extent. Consistent with prostate cancer series of all patient ages, the vast majority of deaths were due to cardiovascular disease (44.2%) and non-prostate cancer deaths (23.1%). In fact, our elderly patients were 60 times more likely to die of these 2 causes compared to prostate cancer. In Kaplan-Meier analysis, overall mortality was related to cardiovascular disease, the total number of comorbidities, a low to lower third normal testosterone, tobacco and the use of ADT in patients with multiple comorbidities and/or CVD (Fig. 2). The relationship between OM, ADT & CVD is consistent with an earlier study from our group [14]. A Fine-Gray analysis demonstrated OM was best predicted by the number of comorbidities. The influence of the total number of comorbidities (Fig. 2c) supports the findings of a prior study of men > = 75 years [15].
In order to maximize the impact of treatment, consultation with cardiology, internal medicine and other appropriate physicians/healthcare providers is essential to correct/control comorbidities to improve overall life expectancy. The International Society of Geriatric Oncology (SIOG) recommends the management of older men be based on individualized health status (biologic age) and not chronologic age [7]. Healthy lifestyles decrease prostate cancer and non-prostate cancer deaths [16]. Cardiovascular disease is highly treatable with improvements in overall survival, but it is not routinely assessed by the uro-oncology team [17]. Initiation of an exercise program to include aerobic and resistance training and cessation of all tobacco products positively impacts overall health [18, 19]. In our current study, a comparison of patients dying within 4 years of brachytherapy and those living more than 14 years following treatment indicated the total number of comorbidities (but not any specific comorbidity) was associated with long-term survival. 56.8% of patients who lived 14 or more years presented with 0–1 comorbidities while only 14.0% presented with 3 or more comorbidities. In contrast, of those who died within 4 years of brachytherapy, 37.1% presented with 0–1 comorbidities and 37.1% presented with at least 3 comorbidities. Daskivich and colleagues reported 14-year other cause mortality of 71% in men > = 75 years of age presenting with 3 or more comorbidities [15]. In our series, patients with > = 3 comorbidities had a 14-year OM rate of 74.9% (Table 3). In the Daskivich study, the number of comorbidities at presentation impacted OM. For all age groups including younger patients, the 14-year OM was 24%, 33%, 46% and 57% in men with 0,1, 2 and > = 3 comorbidities [13]. In our series of men > = 75 years, 14-year OM was 31.3% in men without any comorbidities and significantly increased with a greater number of comorbidities (p < 0.001).
A concern of definitive treatment in elderly patients is poor tolerance. Our elderly patients were treated with the same approach as younger men. No patient underwent therapeutic intervention for hematuria or hematochezia or developed a rectal fistula. From the urinary perspective, 2 patients with a history of a transurethral resection of the prostate developed significant urinary incontinence. Unfortunately, a detailed quality of life evaluation was not included in the current database.
Strengths of our study include the fact that all patients were managed by a single physician with consistent implant and EBRT philosophies and follow-up until death. Shortcomings consist of the single institutional nature of the study, relatively small patient numbers, the lack of information regarding the duration and severity of the comorbid conditions, ADT administered in a non-controlled approach and no current quality of life assessment.
Conclusions
Definitive treatment is warranted in appropriately selected elderly men with clinically localized prostate cancer. Patient selection criteria to include the number of comorbidities must be assessed to maximize oncologic outcomes while minimizing over-treatment. Men with higher risk prostate cancer and no comorbidities are most likely to benefit from definitive treatment regimens.
Acknowledgements
n/a.
Authors’ contributions
Shalini Moningi – concept, writing reviewGrgur Mirić – concept, data curation, formal analysis, investigation, methodology, projectadministration, supervision, validation, writing original draftRobert Galbreath -data curation, formal analysis, investigation, methodology, software, supervision, validationRyan Fiano - data curation, formal analysis, software, validationKent Wallner – analysis, concept, writing reviewMutlay Sayan – formal analysis, writing reviewPeter Orio – concept, writing reviewMartin King - concept, writing review.
Funding
Statistical analysis was supported by a grant from Theragenics Corp.
Data availability
All data is housed at Filemaker (a Google company) and Bethany College.
Declarations
Ethics approval and consent to participate
Approved by the BERACC Bethany Ethical Research & Animal Care Committee. All patients signed an IRB approved consent.
Consent for publication
All patients signed an IRB approved consent.
Competing interests
Shalini Moningi has no conflicts to report.Grgur Mirić has served as a consultant for Theragenics, outside of the submitted work.Robert Galbreath has received a grant from Theragenics for statistical analysis.Ryan Fiano has no conflicts to report.Kent Wallner has no conflicts to report.Mutlay Sayan has no conflicts to report.Peter Orio has received research funding, consulting fees, and stock for Palette Life Sciences, outside of the submitted work.Martin King has received research funding from Palette Life Sciences, Bayer Healthcare, andAstraZeneca, outside of the submitted work.
Footnotes
Publisher’s Note
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data is housed at Filemaker (a Google company) and Bethany College.