Current treatment patterns within 1 year after prostate cancer diagnosis in Korean patients over 75 years old: a retrospective multicenter study

Background We aimed to evaluate the current status of first-line treatment options for prostate cancer in patients aged ≥75 years in Korea. Materials and methods The study included 873 patients diagnosed with biopsy-proven prostate cancer at 5 institutions in Korea from January 2009 to December 2018. Inclusion criteria were aged ≥75 years at diagnosis, prostate biopsy with ≥12 cores, and follow-up period ≥1 year. Clinical data were retrospectively collected from electronic medical records. Results Primary treatment for prostate cancer in patients aged ≥75 years included androgen deprivation therapy (ADT) (n = 614), radical prostatectomy (RP) (n = 114), and radiation therapy (n = 62). Among patients with RP, nine patients received ADT before RP. The RP group was younger with better Eastern Cooperative Oncology Group Performance Status (ECOG PS), lower initial prostate-specific antigen (PSA), Gleason score (GS), max percent positive cores, less positive cores, and less advanced clinical Tumor Node Metastasis (TNM) stage compared with the ADT group. Multivariate analysis showed that age, ECOG PS, and PSA were independent prognostic factors for RP. When the ADT group was classified by therapeutic regimens, the most common therapeutic regimen was maximal androgen blockade (MAB) (n = 571), and leuprolide + bicalutamide (n = 330) was the most common MAB regimen. Multivariate analysis for secondary treatment showed that age, ECOG PS, GS, and clinical N1 or M1 stage were independent predictive factors. Enzalutamide was the most preferred treatment for tertiary treatment. Conclusion In patients with prostate cancer aged ≥75 years, the most common treatment option was MAB, and the leuprolide + bicalutamide was the most common MAB regimen. Age, ECOG PS, and PSA are the useful indicators of surgical treatment, which increased during the study period. Younger patients with high GS and advanced clinical stage were more likely to undergo secondary treatment.


Introduction
The increased proportion of people over 65 years indicates societal aging. 1 In Korea, which became an "aged society" in 2018, the proportion of the population over 65 was 15.8% in 2020. 1,2 According to the complete life tables in the Korean Statistical Information Service, the life expectancy of Korean males is persistently increasing and was 80.5 years old in 2020. 3 In Korea, prostate cancer is one of the most common cancers in men aged 65 years and over, and the incidence of prostate cancer is increasing in recent years. 4 The incidence of prostate cancer peaks at 75e79 years. Men aged 65 years and over account for 77.2% of prostate cases, and men aged 75 years and over account for 35.9% of prostate cases. 4,5 In the National Comprehensive Cancer Network guidelines for prostate cancer, estimated life expectancy and risk stratification are important factors determining treatment modalities 6 , which include radical prostatectomy (RP) in patients with a life expectancy of 10 years or more. 6 Several studies focused on RP in elderly patients. 7e11 An observational study using the National Prostate Cancer Register of Sweden reported that the proportion of patients over 70 years old with localized prostate cancer who underwent RP was lower than the proportion of younger patients who underwent RP; however, an increasing proportion of patients undergoing RP was observed during the study period. 7 Two studies that investigated treatment patterns of Korean patients with prostate cancer reported similar results in patients aged 75 years or older. 8,9 A retrospective study of Korean patients with prostate cancer reported that RP was an appropriate treatment option for the selected patients aged 75 years or older. 10 Another study using National Health Insurance Sharing Service data reported that the patients aged 75 years or older who underwent robot-assisted RP (RARP) for non-metastatic prostate cancer had similar survival rates as patients who underwent radiation therapy (RT). 11 In Korea, prostate cancer more rapidly increased from 2015 to 2019 than from 2009 to 2015. 4 However, most previous studies did not include patients recently diagnosed with prostate cancer from 2015 to 2019. 8e10 Moreover, these studies, except the one that did not include clinical data from prostate cancer 8,9,11 , included clinical data investigated for only RP as the primary treatment. 10 To investigate more recent treatment patterns, including clinical data for prostate cancer, we aimed to evaluate the current status of treatment options for prostate cancer in patients aged 75 years in Korea.

Ethics statement
This retrospective study was performed with the approval of the Institutional Review Board of Dongguk University Gyeongju Hospital (IRB number: 110757-202206-HR-02-02). The study was conducted in accordance with the relevant laws and regulations, good clinical practices, and ethical principles, as described in the Declaration of Helsinki. Informed consent was waived by the board due to the retrospective nature of the study.

Patients
Clinical data were retrospectively collected from electronic medical records of patients diagnosed with prostate cancer at five institutions from January 2009 to December 2019. Inclusion criteria were (i) 75 years or older at time of diagnosis; (ii) diagnosis of prostate cancer with prostate biopsy of 12 or more cores; (iii) prostate cancer with known clinical TNM stage and Gleason score (GS); (iv) follow-up period of more than one year. Of the 881 patients who satisfied the inclusion criteria, seven patients with unknown clinical TNM stage and one patient with an unknown GS were excluded. Thus, 873 patients were enrolled in the study.
Patients were divided according to the primary treatment into androgen deprivation therapy (ADT) (n ¼ 614), RP (n ¼ 114), and RT (n ¼ 62) groups. We analyzed the proportions of patients who received hormonal therapy regimens and maximal androgen blockade (MAB) regimens. We compared the baseline and clinicopathological characteristics of patients who underwent ADP or RP as the primary treatment. We also analyzed the baseline and clinicopathological characteristics in patients who received secondary and tertiary treatments. We compared the baseline and clinicopathological characteristics of patients as well as primary treatment patterns based on the year of diagnosis (2009e2014 vs. 2015e2019), age of diagnosis (75e79 vs. 80 years or older), and clinical stage (localized prostate cancer vs. locally advanced and metastatic prostate cancer).

Statistical analysis
The Student's t-test or ManneWhitney test was used for continuous variables. The Chi-square test or Fischer Exact test was used for categorical variables. Multivariate Cox regression analyses were performed to determine the predicting factors for undergoing RP and secondary treatment. The odds ratio (OR) and 95% confidence interval were determined. All statistical analyses were performed using the Statistical Package for the Social Sciences, version 27.0 (SPSS Inc., Chicago, IL, USA), and P values < 0.05 were considered statistically significant.

Results
We retrospectively reviewed the medical records of 873 patients diagnosed with prostate cancer at five institutions from January 2009 to December 2019. The median age was 78.0 (75.0e94.0) years, the median prostate-specific antigen (PSA) was 18.6 (0.6e6520.0) ng/ml, and the median prostate volume was 37.1 (6.5e224.6) ml. GSs were 8 in 57.4% of patients, and 19.2% of patients had metastatic prostate cancer (Table 1).
Among patients receiving MAB, leuprorelin acetate þ bicalutamide (57.8%) was the most common regimen (Fig. 2). The RP group was younger (76.0 vs. 79.0, P < 0.001) and had a higher body mass index (23.8 ± 3.0 vs. 23.0 ± 2.7, P ¼ 0.004) compared with age and body mass index in the ADT group. In addition, the Eastern Cooperative Oncology Group Performance Status (ECOG PS), initial median PSA (7.9 vs. 26.8 ng/ml, P < 0.001), GS, median number of positive cores, median max percent of positive cores, and advanced clinical TNM stage (P < 0.001) were lower in the RP group than these parameters in the ADT group (Table 2). Among the RP group, 7.9% of patients underwent neoadjuvant hormone treatment and 4.4% of patients underwent adjuvant hormone treatment.  According to the multivariable logistic regression analysis, the predicting factors for undergoing RP as the primary treatment were age (OR 0.653, P < 0.001), ECOG PS 1 (OR 0.066, P < 0.001), and serum PSA level (OR 0.943, P < 0.001). No other factors were associated with RP as the primary treatment ( Table 3).
Compared to baseline data, clinicopathological characteristics and primary treatment patterns in 2009e2014 and 2015e2019 according to age and clinical stage group, localized prostate cancer, and the age 75e79 group in 2015e2019 had a significantly lower ratio of ADT and a higher ratio of RP and RT as the primary treatments than in 2009e2014 (Fig. 3). The ratio of ECOG PS 0 in 2015e2019 was significantly higher in localized prostate cancer and the 75e79 age group (Table S4).

Discussion
In the present study, the most common treatment option for prostate cancer in patients over 75 years was MAB. In previous studies, most patients over 75 years underwent ADT for prostate cancer, and the ratio of patients who underwent RP was lower in older patients than the ratio in younger ages. 8,9 Younger age and lower ECOG PS and serum PSA levels predicted primary treatment of prostate cancer with RP in this study. Moreover, localized prostate cancer and the 75e79 age group in 2015e2019 had significantly higher ratios of ECOG PS 0 and RP as the primary treatments than those in 2009e2014. RP is indicated for clinically localized patients with prostate cancer and with a life expectancy of 10 years or more. 6 The ratio of localized prostate cancer in patients over 75 years in the present study was similar to the ratio of localized prostate cancer in the Korea Central Cancer Registry (KCCR) annual report (56.0% vs. 53.0%). However, the ratio of metastatic prostate cancer in patients over 75 years in our study was higher than the ratio of metastatic prostate cancer in the KCCR annual report (19.2% vs. 10.1%). 4 Increased ECOG PS is associated with shorter median survival periods in patients with advanced cancer . 12 Shorter life expectancy due to older age and/or increased ECOG PS and a higher rate of metastatic prostate cancer may explain the lower rate of RP in patients with prostate cancer and 75 years or older. 4,6,12   The present study showed that the proportion of RP increased from 11.6% in 2009e2014 to 15.8% in 2015e2019, and the proportion of ADP decreased from 82.9% in 2009e2014 to 75.3% in 2015e2019. Several recent studies showed that the relative portion of patients with prostate cancer undergoing surgery, especially RARP, rapidly increased, and the portion of patients undergoing ADT decreased slightly from 2003 to 2014. 8,9 Life expectancy is continuously increasing; the age with a 10year life expectancy increased from 75 years in 2009 to 77 years in 2019. 3 Although the proportions of localized and regional prostate cancers did not dramatically increase from 2009 to 2019 (75.7% vs. 78.5%), the proportion of patients with prostate cancer and aged 75 years or older increased (27.4% vs. 35.9%). 13,14 In the present study, the ratios of patients who underwent RP in the clinical stage T3 or more was 13.8% in 2009e2014 and 23.5% in 2015e2019. However, the ratio of patients who underwent RP in the clinical N or M stage did not increase. A retrospective study that evaluated the changing trend of RARP also reported that patients who underwent RARP from 2013 to 2019 had more unfavorable disease characteristics. 15 Recently, the indications for RP were extended from localized or regional prostate cancer to nodepositive or metastatic prostate cancer. 16e18 In addition, the role of cytoreductive RP for metastatic prostate cancer is being investigated in several clinical trials. 19 Several studies compared complications, functional outcomes, and oncological outcomes in patients who underwent RARP versus RRP. 20e23 Two meta-analyses demonstrated that RARP had lower complication rates and better functional outcomes than RRP. 20,21 One meta-analysis reported that biochemical recurrence was lower in patients with RARP, but recurrence-free survival was similar between the two groups. 21 A prospective, multicenter, controlled, non-randomized trial comparing RARP with RRP reported lower erectile dysfunction, positive surgical margins, biochemical recurrence, and prostate cancer-specific mortality for RARP. 22 However, a randomized clinical phase 3 study comparing RARP with RRP reported similar functional outcomes between the two groups and lower biochemical recurrence at 24 months. 23 The increasing life expectancy, the expansion of indications for surgical treatment, and the advantages of RARP may have increased the portion of prostate cancer patients aged 75 years or over undergoing surgical treatment, especially RARP. 3,5,8,14,16,17,19e23 Among MAB regimens, leuprolide þ bicalutamide was the most common in the present study. The most common luteinizing hormone-releasing hormone agonist for combination and monotherapy was leuprolide (57.8%), followed by goserelin (21.8%) and triptorelin (7.7%). A multi-institutional, prospective, observational study about hormone treatment for prostate cancer patients in Korea reported similar results. 24 Although the authors reported that the efficacy of leuprorelin was lower than other luteinizing hormone-releasing hormone agonists, leuprorelin was the most common hormone therapy for prostate cancer; the authors hypothesized that this trend was due to cost-effectiveness. 24 This study had several limitations. First, this study was retrospective, which may cause selection bias. Second, patients in this study came from only five institutions in Korea and may not reflect all prostate cancer patients in Korea. Last, this study contained clinical stage and biopsy data, but survival outcomes were not included. Thus, we could not estimate survival outcomes. Further studies, including survival outcome studies with more patients, are warranted.
In conclusion, the most used treatment option in patients with prostate cancer over 75 years was MAB. Among MAB regimens, leuprolide þ bicalutamide was the most common. Age, ECOG PS, and PSA may be the useful indicators of surgical treatment, and the proportion of patients who underwent surgical treatment increased. Younger patients with high GSs and advanced clinical stages are more likely to receive secondary treatment.