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Androgen deprivation therapy alone is commonly performed for metastatic prostate cancer but is generally not recommended for the treatment of high-risk localized or locally advanced prostate cancer.
- prostate cancer
- androgen deprivation therapy
1. Introduction
Prostate cancer (PC) is the most common cancer in men and the leading cause of cancer-related deaths in developed countries [1][2]. Most PC deaths are caused by metastatic disease [3]. Approximately 10% of new PC cases are diagnosed with distant metastasis [4][5][6]. The development and dissemination of prostate-specific antigen (PSA) screening have contributed to early PC detection, which in turn has reduced PC-related mortality [7][8][9][10]. However, approximately 15% of newly diagnosed PCs are high-risk PCs [11]. While localized PC generally has a good prognosis, high-risk PC has a significantly worse prognosis than low- and intermediate-risk PC, with a 15-year PC-specific mortality rate of 22–38% [11][12][13]. Guidelines differ slightly in their definition of high-risk PC, including locally advanced PC (Table 1). In the D’Amico risk classification, the European Association of Urology (EAU) guidelines, and European Society for Medical Oncology (ESMO) guidelines, patients are classified as high-risk if they meet clinical stage T2c or a PSA level of ≥20 ng/mL or Gleason score of 8–10, while the National Comprehensive Cancer Network (NCCN) guidelines classify patients as high-risk at clinical stage T3 or higher [14][15][16][17]. The EAU guidelines classify locally advanced PC at clinical stage T3 or higher or clinical stage N1, and the NCCN guidelines classify very high-risk at clinical stage T3b or higher or primary Gleason pattern 5 or >4 cores with grade group 4 or 5 [15][16]. Briefly, patients with clinical stage T2c, a PSA level of ≥20 ng/mL, or a Gleason score of 8–10 are considered to have high-risk PC. Although each guideline differs slightly, radical prostatectomy (RP) + extended pelvic lymph node dissection (ePLND) or radiation therapy (RT) + long-term androgen deprivation therapy (ADT) is recommended for the treatment of high-risk or locally advanced PC, and ADT alone is currently indicated in a few cases [15][16][17]. However, ADT has been used aggressively for localized PC in Japan. According to data from 10,280 PC patients diagnosed in Japan in 2004, 41% of non-metastatic castration-sensitive prostate cancer (nmCSPC) patients received ADT as initial treatment [5].
Table 1. Definition of high-risk prostate cancer.
| Risk | Clinical Stage | Initial PSA | Gleason Score | References | |||||
|---|---|---|---|---|---|---|---|---|---|
| D’Amico et al. | High | ≥T2c | or | >20 ng/mL | or | ≥8 | [14] | ||
| NCCN 2021 | High | T3a | or | >20 ng/mL | or | Grade Group 4 or Grade Group 5 | [15] | ||
| Very high | T3b/T4 | or | or | Primary Gleason pattern 5 or > 4 cores with Grade Group 4 or 5 | or | 2 or 3 high-risk features | |||
| EAU 2020 | High | T2c | or | >20 ng/mL | or | ≥8 | [16] | ||
| Locally advanced | T3/T4 or N1 | and | Any | and | Any | ||||
| ESMO 2020 | High | ≥T2c | or | >20 ng/mL | or | ≥8 | [17] |
PSA = Prostate specific antigen; NCCN = National Comprehensive Cancer Network; EAU = European Association of Urology; ESMO = European Society for Medical Oncology.
2. ADT
2.1. History of ADT
After Huggins and Hodges reported the efficacy of castration therapy, ADT became the gold standard for advanced PC [18]. Surgical castration had been the only method of castration, but Schally and Guillemin elucidated the structure of GnRH, which led to the development of GnRH agonists, and medical castration became possible [19]. Studies have reported the efficacy and tolerability of GnRH agonists as a first-line treatment for advanced PC and concluded that the survival rate, disease progression, and time to treatment failure are comparable between GnRH agonist therapy and orchiectomy [20][21][22][23]. Surgical castration is a simple and cost-effective outpatient procedure, while the advantage of medical castration is the avoidance of surgery [20][21][22][23][24]. In recent years, the rate of surgical castration has been reported to be less than 9% [24]. Although castration reduces serum testosterone levels by approximately 90%, 20–40% of dihydrotestosterone (DHT) remains in human PC tissue [25][26][27]. As this residual androgen may cause inadequate treatment of PC or relapse, CAB therapy, which combines ADT with an antiandrogen drug, has been proposed [28][29][30]. Recently, GnRH antagonists are developed. GnRH agonists have been reported to result in a transient increase in testosterone levels that occurs early in the administration, which is called a testosterone surge that can cause urinary tract obstruction and spinal cord compression [31][32][33]. GnRH antagonists do not cause testosterone surges, and testosterone levels reach castration levels early, so they may be particularly useful in patients with symptomatic metastatic PC [34]. In addition, ADT has made progress with the development of the new androgen receptor signaling-targeted agent (ARSTs), such as enzalutamide, abiraterone acetate, apalutamide, and darolutamide [35][36][37][38]. The effects of ADT are generally not permanent and eventually lead to castration-resistant PC (CRPC) [6]. The treatment for CRPC includes alternative ADT [39], ARST [35][36][37][38], and chemotherapy such as docetaxel [40][41] and cabazitaxel [42][43]. ADT is effective in improving patients’ quality of life by reducing bone pain, pathological fractures, spinal cord compression, and ureteral obstruction, which are symptoms specific to advanced PC, such as bone metastases or local enlargement of PC [18][44][45]. However, ADT has various adverse effects, such as hot flashes [46][47][48][49][50], sexual dysfunction [46][49][50][51][52], breast enlargement [48][49][53][54], depression [49][55], dementia [56][57][58][59][60][61], osteoporosis [62][63][64][65][66], obesity [46][67], diabetes [68][69][70][71][72][73], and cardiovascular (CV) toxicity [68][74][75][76][77][78][79][80]. Dementia, osteoporosis, and CV toxicity are important side effects of ADT in older patients. Researchers summarize these AEs for older patients with PC in the next section.2.2. ADT for High-Risk Localized and Locally Advanced PC
Various guidelines do not recommend ADT alone as an initial treatment for high-risk or locally advanced PC [15][16][17]. However, in clinical practice, some patients, especially older ones, are treated with ADT alone as the initial therapy. In the USA, the use of GnRH agonists has increased since the 1990s [81], and as of 2009, 22% of patients with localized PC aged >66 years were being treated with ADT alone [82]. In Japan, approximately 30% of patients with localized PC were treated with ADT alone [5]. As shown in Table 2 and Table 3, many studies have reported on the efficacy of ADT alone for localized PC, but worldwide, there are more negative reports.Table 2. Negative data of ADT for high-risk localized and locally advanced prostate cancer.
| Study | Study Specification | Patient Characteristics | Size | Findings | References | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Merglen et al. (2007) | retrospective cohort study | prospective studyPatients with localized PC treated with either total prostatectomy, radiation therapy, watchful waiting, hormone therapy, or other treatment | 844 | Patients who received ADT alone already had an increased risk of PCSM at 5 years (HR 3.5, 95% CI 1.4–8.7) | [83 | Patients with newly diagnosed locally advanced or localized PC who have undergone CAB] | |||||||
| 57 | In patients with stage T2–T3 cancer who continued CAB for more than 6.5 years and discontinued treatment there were only two cases of PSA elevation. Long-term continuous CAB was suggested to be a possibility for long-term control or cure of localized PC | [ | 88 | ] | Lee et al. (2018) | retrospective study | Patients diagnosed with localized PC who underwent ADT or treatment-free follow-up | 340 | In clinically unfavorable localized intermediate- and high-risk PC, initiation of ADT within 12 months of diagnosis was not associated with improved 5-year all-cause mortality or PCSM compared with patients who received no conservative treatment | [84] | |||
| Akaza et al. (2006) | prospective cohort study | Patients with newly diagnosed locally advanced or localized PC who have undergone ADT | 151 | In men with localized or locally advanced PC, primary ADT inhibited PC progression and resulted in a life expectancy similar to that of the normal population | [89] | Lu-Yao et al. (2008) | retrospective cohort study | Patients diagnosed with localized PC who underwent ADT or treatment-free follow-up | 19,271 | ADT is not associated with improved survival among the majority of elderly men with localized prostate cancer when compared with conservative management | [ | ||
| Kawakami et al. (2006) | retrospective cohort study | 85 | ] | Newly diagnosed localized PC patients with or without ADT | 7044 | The use of ADT therapy appeared to control disease in the majority of patients who received it, at least for an intermediate period | [90] | Potosky et al. (2014) | retrospective cohort study | Newly diagnosed patients with localized PC | 15,170 | ADT was associated with neither a risk of all-cause mortality (HR 1.04, 95% CI 0.97–1.11) nor PCSM (HR 1.03, 95% CI 0.89–1.19). | [86] |
| Akaza et al. (2010) | retrospective cohort study | Patients with newly diagnosed locally advanced or localized PC who have undergone ADT | 15,461 | ADT resulted in a long-term survival rate comparable to the general population | [91] | Lu-Yao et al. (2014) | retrospective cohort study | Patients aged 66 years or older with localized PC who did not receive curative treatment | 66,717 | ADT is not associated with improved long-term overall or disease-specific survival for men with localized PC. | [87] | ||
| Sammon et al. (2015) | retrospective cohort study | Newly diagnosed patients with locally advanced or localized PC | 46,376 | There was an increased risk of all-cause mortality in the ADT group compared to the observation group (HR 1.37, 95% CI 1.20–1.56) | [82] |
ADT = Androgen deprivation therapy; PC = Prostate cancer; PCSM = Prostate cancer specific mortality; HR = Hazard ratio; CI = Confidence interval.
Table 3. Positive data of ADT for high-risk localized and locally advanced prostate cancer.
| Study | Study Specification | Patient Characteristics | Size | Findings | References |
|---|---|---|---|---|---|
| Labrie et al. (2002) | |||||
| Matsumoto et al. (2014) | |||||
| retrospective cohort study | Patients with newly diagnosed locally PC at intermediate to high risk who have undergone ADT | 410 | When prostate cancer with no capsular invasion and a GS of less than 8 was treated with ADT, the expected survival rate was similar to that of the general population | [ | 92] |
| Studer et al. (2014) | randomized controlled trial | PC patients without distant metastasis treated with immediate or delayed ADT | 985 | Deferred ADT was inferior to immediate ADT in terms of overall survival (HR 1.21; 95% CI 1.05–1.39) | [93] |
| Nguyen et al. (2011) | meta-analysis of randomized controlled trial | Patients diagnosed with PC | 4141 | ADT was associated with lower PCSM (443/2527 vs. 552/2278 events; RR, 0.69; 95% CI, 0.56–0.84; p < 0.001) and lower all-cause mortality (1140/2527 vs. 1213/2278 events; RR, 0.86; 95% CI 0.80–0.93; p < 0.001) | [80] |
ADT = Androgen deprivation therapy; PC = Prostate cancer; CAB = Combined androgen blockade; PSA = Prostate specific antigen; GS = Gleason score; HR = Hazard ratio; PCSM = Prostate cancer specific mortality; CI = Confidence interval; RR = Relative risk.
