Version May 2024
INTRODUCTION — Prostate cancer in older males is particularly important because of the high incidence and prevalence of disease and mortality in this group of patients. Management of prostate cancer in males over the age of 70 can be complicated by the comorbidity, competing mortality, and health status issues specific to this group; in addition, there are generally limited data on the efficacy of newer treatments because older patients are underrepresented in clinical trials in prostate cancer.
The initial treatment for older males with competing morbidity and mortality who have localized prostate cancer or advanced disease will be reviewed here. The approach to these issues in younger patients is reviewed separately:
●(See "Initial approach to low- and very low-risk clinically localized prostate cancer".)
●(See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer".)
●(See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
EPIDEMIOLOGY — The public health burden of treating older males with both early and advanced prostate cancer is substantial and is expected to increase over the coming decades:
●The incidence of prostate cancer is strongly correlated with age and disproportionately affects older adults. Prostate cancer incidence rates rapidly rise with increasing age starting around age 50 years, with the highest rates seen in those aged 70 to 80 years (figure 1). Thus, the estimated prevalence for males aged 75 years or greater is over one million males [1]. In the United States in 2018, 58 percent of new cases were diagnosed in males 65 years of age or older [2].
●Prostate cancer is the third most common cause of cancer death among males aged 80 years and older [3]. Although the case-fatality rate of prostate cancer is quite low, deaths occur disproportionately in older males, owing to the long natural history of the disease. Thus, 41 percent of males who die of prostate cancer are between age 75 and 84 years, and 30 percent are 85 years or older.
●The median age at prostate cancer diagnosis is 66, but the median age of males who develop metastatic disease is considerably older, and the median age of those who die from the disease is 80 [2].
●Given the aging population, it is estimated that the total number of patients with prostate cancer aged 70 and older will increase between 2018 and 2030 from 585,000 to 778,000 in the United States [4].
PATIENT CLASSIFICATION BASED ON HEALTH STATUS — Geriatric patients often have less functional independence, a greater number of medical comorbidities and associated medications, a decline in cognitive and nutritional status, and/or a lack of social support [5]. (See "Systemic chemotherapy for cancer in older adults", section on 'Challenges specific to older-adult patients'.)
As a result, treatment decisions for both early and advanced-stage prostate cancer must take into account the risk of dying from prostate cancer (tumor grade and stage), as well as the risk of dying from another cause (ie, comorbidities, overall health status), the risks of treatment, and patient preferences. These issues have been integrated into recommendations for the management of older males with prostate cancer in the consensus-based guidelines of the International Society of Geriatric Oncology (SIOG), which have been updated several times, most recently in 2019 [6-8]. The 2019 guidelines were fully endorsed by the European Association of Urology (EAU) and the European Society for Radiotherapy and Oncology (ESTRO), and the recommendations are now referred to as the EAU/ESTRO/SIOG guidelines [8].
The most recent recommendations emphasize that treatment decisions should be based on health status rather than age [8]. The recommendations include several standardized assessments of health status, which can be easily and quickly administered in the clinical setting (table 1). These include the following:
●An initial assessment of health status using the Geriatric 8 (G8) screening instrument [9]. This assessment incorporates eight different parameters, including food intake, weight change over the last three months, mobility, neuropsychological issues, body mass index, use of three or more medications per day, the patient's self-assessment of his health status, and age. Individual scores are provided for specific answers, and based on the total score, patients were divided into those deemed "fit" (score 14 or lower out of 17) and those considered to have significant impairment (score >14), who therefore, might benefit from a comprehensive geriatric assessment (CGA).
●Screening for cognitive impairment using the Mini-Cog test is also recommended [10]. The Mini-Cog test consists of a three-word recall (with 1 point for each correct word) and a clock-drawing test (with 2 points for a correctly drawn clock and 0 points for an abnormal clock) that can be completed in five minutes. A cutoff point of ≤3 out of 5 points indicates a need for a full evaluation for dementia.
●For patients with impairment on the G8 health assessment (ie, a score of ≤14 out of 17), the second step is a CGA [6]. There is no uniform CGA measurement tool. American Society of Clinical Oncology (ASCO) guidelines provide a minimum dataset for practical assessment of vulnerabilities in older patients with cancer (table 2) [11]. The guidelines also include recommendations for specific interventions guided by the geriatric assessment (table 3). A CGA is also recommended by the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for Older Adult Oncology [12]. The practical aspects of conducting a CGA are addressed in detail elsewhere. (See "Comprehensive geriatric assessment for patients with cancer".)
At minimum, the following domains should be assessed:
•Comorbidity – An evaluation of an individual's comorbidities (ie, Cumulative Illness Rating Score for Geriatrics [CIRS-G]) is used to determine whether the impairment is reversible or irreversible. The CIRS-G rates comorbid conditions on a 0 to 4 scale:
-Grade 0 – No problem
-Grade 1 – Current mild problem or past significant problem
-Grade 2 – Moderate disability or morbidity; requires first-line therapy
-Grade 3 – Severe/constant significant disability; uncontrollable chronic problem
-Grade 4 – Extremely severe; immediate treatment required; end-organ failure; severe impairment in function
•Dependence – Dependence includes an assessment of activities of daily living (ADLs), which address home independence, as well as instrumental activities of daily living (IADLs), which assess independence in the community setting (table 4). The IADL scale can be modified further; the SIOG recognizes that all eight categories of the IADL scale may not be appropriate for a male population and thus allows for only four items to be used in the screening [13]:
-Financial management
-Medication management
-Use of transportation
-Use of the telephone
•Nutritional status – An individual's nutritional status can be estimated by determining weight loss over the preceding three months:
-Good nutritional status – Weight loss <5 percent
-Risk of malnutrition – Weight loss 5 to 10 percent
-Severe malnutrition – Weight loss >10 percent
The CGA needs to be followed by specific interventions, implemented in response to any vulnerabilities that are identified (table 3) [14]. Based on this information, a patient can be categorized into one of three groups:
●Fit/healthy – Defined as having a G8 score >14 out of 17, no comorbidities, no dependence, no malnutrition, and no cognitive impairment.
●Vulnerable – Patients have either some impairment in ADLs, moderate malnutrition, or moderate comorbidities. Following appropriate geriatric intervention, these patients should receive standard treatment for their prostate cancer.
●Frail – Older patients who either are dependent on multiple ADLs or have severe malnutrition or severe comorbidities. Although geriatric intervention may be beneficial for some patients, treatment must generally be adjusted to take into account the patient's impairment.
A decision-tree approach to assessing health status in older males with prostate cancer to inform treatment decisions is presented in the algorithm (algorithm 1).
The NCCN consensus-based guidelines for Older Adult Oncology support the use of a CGA, with similar recommendations that state health rather than age should be the determinant of treatment option in older males with prostate cancer [12].
Predicting life expectancy — A related issue, both for issues of screening and management of patients in whom prostate cancer has been diagnosed, is that clinicians have only limited ability to predict life expectancy in males with localized prostate cancer [15,16]. Because life tables do not consider factors other than an individual's chronologic age, they do not accurately predict survival in males with multiple comorbidities. In a study of males with prostate cancer, life expectancy tables overestimated survival by 32 percent in those males with a Charlson Comorbidity Index ≥3 (table 5) [17]. Nomograms are available to predict 10-year life expectancy in males with localized prostate cancer that may be more accurate than life tables because they take into account comorbidities [18]. However, updated guidelines from the EAU/ESTRO/SIOG recommend the use of ePrognosis in the setting of localized prostate cancer to estimate non-cancer-specific life expectancy and aid in decision making [8]. (See "Survival estimates in advanced terminal cancer".)
PROSTATE CANCER SCREENING — The role of prostate cancer screening is controversial, both in older and in younger males. The issues and screening guidelines are discussed separately. (See "Screening for prostate cancer", section on 'Discontinuing screening'.)
TREATMENT
Risk assessment — The initial management plan for males with newly diagnosed prostate cancer depends on a pretreatment assessment of the risk of locoregional recurrence or disseminated disease combined with patient age, life expectancy, overall medical condition (including performance status and comorbidities), presence or absence of symptoms, and patient preferences to make decisions about the optimal treatment for an individual patient. Key factors in this assessment include clinical staging of the extent of disease (table 6 and table 7), the pretreatment serum prostate-specific antigen (PSA), the Gleason score in the pretreatment biopsy, and in some cases, the results of pretreatment imaging studies. (See "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'Risk stratification'.)
Based on this information and the results of additional studies as may be indicated, patients are divided into several categories, which provide the basis for treatment decisions (table 8). These categories were based on the D'Amico classification [19], which is still used in the consensus-based treatment recommendations of the European Association of Urology (EAU)/European Society for Radiotherapy and Oncology (ESTRO)/International Society of Geriatric Oncology (SIOG) [8]. (See "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'Risk stratification'.)
Localized disease — As is the case for younger males, potentially curative treatment options for the older man with localized prostate cancer include radiation therapy (RT; both external beam and brachytherapy) and radical prostatectomy. Other standard options include active surveillance (ie, careful monitoring with PSA, rectal examinations, and periodic biopsies, with potentially curative treatment on progression) or watch and wait (observation until the patient becomes symptomatically progressive, then treatment is instituted). Androgen deprivation therapy (ADT) has also been used [20,21], although it is discouraged as primary therapy in males with lower risk disease, owing to an increase in all-cause mortality. Its use is also discouraged in males with unfavorable-risk disease because of concerns about undertreatment [21]. (See "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'Androgen deprivation therapy alone' and "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Benefits of definitive treatment'.)
Several publications have reported on the treatment options that are actually used for older males [20,22-25]:
●Data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) indicate that, for males over the age of 75 years, the use of ADT is declining among males with low-risk disease [25]. For those with low-risk disease, the proportion undergoing surveillance was 76 percent, and primary ADT declined from approximately 30 percent in 2000 to 2004 to <5 percent. On the other hand, for those with high-risk disease over the age of 75 years in the CaPSURE database, primary ADT remained the most common treatment, utilized in 67 percent of males.
●Yang et al used the National Cancer Database (NCDB) to examine definitive therapy (prostatectomy or RT) among 400,000 males diagnosed with intermediate- or high-risk prostate cancer between 2004 and 2012 [20]. With increasing age and comorbidity, patients were less likely to receive definitive treatment, and more than 40 percent of males over the age of 80 did not receive definitive treatment with surgery or RT. Compared with males who received definitive treatment, those who did not receive definitive therapy were more likely to die within one year of diagnosis, regardless of age or prostate cancer disease risk, suggesting that decision making was reasonably aligned with estimated life expectancy [21]. However, over one-half of those males with high-risk disease who did not receive definitive therapy went on to receive ADT instead. Given that the benefits of ADT are associated primarily with advanced rather than localized disease [26-28], that primary ADT for localized prostate cancer is associated with decreased overall survival and notable side effects (metabolic syndrome, fractures, and cognitive, cardiovascular, and sexual dysfunction), and that safer, more effective treatment approaches exist (eg, RT), the authors concluded that definitive therapy was underused and ADT was widely overused in this population.
Life expectancy and impact of disease on survival — Treatment decisions for males who present with localized prostate cancer need to consider both the life expectancy of the patient independent of his prostate cancer and the natural history of the prostate cancer. Data on the natural history of untreated prostate cancer indicate that, although there are more deaths due to competing risks in males over the age of 70 years, especially in those with lower grade disease, a significant number of males over the age of 70 at diagnosis will eventually die of prostate cancer. The decision of whether or not to proceed with aggressive therapy for localized disease thus should incorporate not only the patient's age, but also the presence or absence of significant comorbidity, as well as the aggressiveness of the prostate cancer, as estimated by risk stratification.
Two large studies illustrate the relationships between age, comorbidity, and the natural history of prostate cancer:
●A study from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database analyzed the risk of prostate cancer-specific mortality in 31,137 males ≥65 years old diagnosed with T1 to T2 disease between 1992 and 2009 [29]. All males were initially managed conservatively, without either definitive therapy (surgery, RT, cryotherapy) or ADT within six months of the original diagnosis. For males with Gleason 5 to 7 disease, the 15-year prostate cancer-specific mortality rates for males aged 65 to 74 and those ≥75 years were 5.7 and 10 percent, respectively. For those with Gleason 8 to 10 disease, the 15-year prostate cancer-specific mortality rates were 22 and 27 percent, respectively. However, 24 and 38 percent of males, respectively, ultimately received ADT.
●A study from the SEER database analyzed outcomes in 3183 males who were included in the Prostate Cancer Outcomes Study (PCOS) [30]. These males were diagnosed with localized disease between 1994 and 1995 and were followed for 14 years. Subjects were assessed for the presence of 12 major comorbidities at presentation (table 9). Outcomes were assessed as a function of age (≤55, 56 to 65, 66 to 75, or ≥76 years), number of comorbidities at presentation (0, 1, 2, or ≥3), tumor risk category (low, intermediate, or high), and treatment (aggressive [surgery, RT] versus nonaggressive [ADT] alone, watchful waiting).
At a follow-up of 14 years, the cumulative mortality rates from all causes other than prostate cancer were 24, 33, 46, and 57 percent for males with 0, 1, 2, or ≥3 comorbidities. By contrast, the rates of prostate cancer mortality at this same time point were 3, 7, and 18 percent for males with low-, intermediate-, and high-risk disease (figure 2).
The risk of prostate cancer mortality was further analyzed based on whether patients were initially managed with aggressive treatment (surgery, RT) or other approaches (watchful waiting, ADT). Males with no comorbidities or only one comorbidity treated with ADT or watchful waiting had a statistically significant increase in risk of prostate cancer mortality compared with those treated aggressively (hazard ratios [HRs] 2.4 and 2.2, respectively). The risks for those with two or three comorbidities managed conservatively were not statistically significant (HRs 1.6 and 1.5, respectively).
As noted above, year 2019 consensus-based guidelines from the EAU/ESTRO/SIOG recommend the use of ePrognosis in the setting of localized prostate cancer to estimate non-cancer-specific life expectancy and aid in decision making [8]. (See 'Predicting life expectancy' above.)
Active surveillance — Patients with very low- and low-risk disease are less likely to derive benefit from immediate intervention than are patients with higher risk disease. (See "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'Clinically localized, NCCN very low risk' and "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'Clinically localized, NCCN low risk'.)
An approach of careful monitoring, with delayed definitive intervention if there is evidence of progression, is an appropriate option for many patients with very low- and low-risk disease and for some males with favorable intermediate-risk disease. (See "Localized prostate cancer: Risk stratification and choice of initial treatment", section on 'Clinically localized, NCCN intermediate risk'.)
The criteria for patient selection for active surveillance and the components of monitoring for disease progression during active surveillance are discussed separately. (See "Active surveillance for males with clinically localized prostate cancer".)
Versus watchful waiting — Active surveillance must be distinguished from "watchful waiting," which is based on the premise that some males will not benefit from definitive treatment of their localized prostate cancer. For patients managed with watchful waiting, the decision is made at the outset that the patient is not a candidate for definitive therapy and to provide palliative treatment (typically ADT) or transurethral resection of the prostate for urinary obstruction if and when symptomatic progression requires therapy. Watchful waiting may be an acceptable alternative for males with a short life expectancy based on age and/or substantial comorbidity.
Definitive local therapy
Radical prostatectomy — Radical prostatectomy may be an appropriate option for males with low-, intermediate-, or high-risk prostate cancer. (See "Radical prostatectomy for localized prostate cancer".)
Efficacy in older males — Assessing the effectiveness of radical prostatectomy in older males with localized prostate cancer is difficult.
Although one randomized trial found that radical prostatectomy in males with localized prostate cancer improved disease-specific survival compared with watchful waiting, the study excluded males over age 75 years [31,32]. In the latest analysis, radical prostatectomy significantly improved cancer-specific survival and reduced the risk of distant metastases, both in males under the age of 65 and in those 65 and older [32]. However, among males 65 years of age or older at diagnosis, the between-group differences were smaller for all investigated endpoints. (See "Radical prostatectomy for localized prostate cancer", section on 'Survival impact of radical prostatectomy'.)
Observational data do support a role for radical prostatectomy in selected patients [33-39]. As an example, in a study of 4500 males undergoing surgery, 17 percent of whom were older than 70 years, higher grade and higher stage disease was seen in those aged 70 or greater compared with younger cohorts [34]. Although unadjusted disease-specific survival was worse in those aged ≥70 years, age was not a significant predictor of survival on multivariate analysis that incorporated stage and grade. This is similar to other series that found worse pathologic characteristics at radical prostatectomy in older patients [35,36] but similar or better disease-specific survival compared with younger cohorts [35-37]. In another series of 386 males over the age of 70 years, the 15-year prostate cancer-specific and overall survival rates were 90 and 69 percent, respectively [38]. This is better than in a population-based cohort of males over the age of 70, in which the 10-year overall survival rate for males undergoing radical prostatectomy was 59 percent [39].
A predictive model that included an individual's comorbidities was developed to improve the accuracy of predicting overall mortality in males with prostate cancer undergoing surgery [40]. This model incorporates Gleason grade, serum PSA, and Charlson Comorbidity Index (table 5) to illustrate the impact of the degree of comorbidity on overall survival in males over the age of 70 years who undergo radical prostatectomy (table 10).
Side effects — One of the biggest concerns with radical prostatectomy in older males is the higher rate of complications compared with younger patients, particularly related to urinary and sexual function. As an example, in one large series, the rate of complications increased progressively with age (4, 7, 9, and 14 percent for ages 40 to 49, 50 to 59, 60 to 69, and ≥70 years, respectively) [41]. (See "Radical prostatectomy for localized prostate cancer", section on 'Functional outcomes'.)
Several studies have reported higher rates of urinary and sexual dysfunction in older males. In a population-based study, frequent urinary leakage was significantly less common at two years postoperation in males <74 years of age compared with those 75 to 79 years (5 to 10 versus 27 percent, p = 0.03) [42]. Similarly, potency rates were lower in males 75 to 79 years compared with those under age 60 years (19 versus 39 percent). This population-based study also collected data on males treated conservatively. Compared with those treated surgically or with RT, those treated conservatively had fewer urinary and bowel issues at two years [43].
Older males may require secondary interventions more frequently following radical prostatectomy [44]. Compared with young males (age <50 years), a higher proportion of males over the age of 70 years required treatment for anastomotic strictures (10.8 versus 5.8 percent) or placement of artificial urinary sphincters (2.5 versus 0.5 percent). Data from CaPSURE show that males over the age of 65 are less likely to return to potency, continence, and physical health one year after radical prostatectomy [45]. Although single-institution series report higher overall continence and potency rates compared with multi-institution databases, such reports still suggest lower rates in older as compared with younger males [41,46,47].
Radiation therapy — RT may be an appropriate option for males with low-, intermediate-, high-, or very high-risk disease. (See "External beam radiation therapy for localized prostate cancer" and "Brachytherapy for low-risk or favorable intermediate-risk, clinically localized prostate cancer".)
Disease control in older males — RT is used more commonly than radical prostatectomy for treatment of older males with localized prostate cancer [23,48,49].
In one study of 381 males aged 75 years or older, external beam RT was associated with worse prostate cancer-specific survival in males with high-risk disease [50]. Another study of 2474 males with localized disease receiving either brachytherapy alone or brachytherapy with neoadjuvant ADT found increased overall mortality in older males (≥73 years, n = 1268) receiving combined treatment (adjusted HR 1.24, 95% CI 1.01-1.53) [51]. This increased overall mortality was not seen in males younger than 73 years of age (p = 0.34). In this study, only 12 percent of males had high-risk disease, and prostate cancer-specific survival was not reported. Other studies have not found advanced age to be associated with biochemical recurrence after RT [52,53].
The effect of comorbidity, rather than age, on survival has been studied following RT for prostate cancer. A randomized study of external beam RT with or without six months of ADT found that the survival advantage for intermediate- and high-risk patients was only seen in those with minimal or no medical comorbidity [54-56]. At a median follow-up of 16.6 years, RT plus ADT was associated with better overall survival than RT alone for the 157 males with no or minimal comorbidity (15-year survival rate 43.8 versus 30.5 percent, p = 0.04). By contrast, for the 49 males with moderate or severe comorbidity, RT plus ADT was associated with worse overall survival (15-year survival rate 8.3 versus 20.0 percent, p = 0.07). In a separate study of 1978 males with intermediate-risk disease aged 66 to 75 years (median 71 years) undergoing RT, the role of cardiovascular disease in survival outcomes was explored [57]. Males with cardiovascular disease had a reduction in the risk of prostate cancer-specific mortality (HR 0.20, 95% CI 0.04-0.99), perhaps due to competing risks for mortality.
In contrast to these studies of males with comorbidities, analyses of healthy males have suggested that aggressive RT is beneficial for older males with high-risk disease. In a retrospective study of 764 healthy older males (age ≥65 years) with high-risk disease, brachytherapy alone was compared with brachytherapy combined with external beam RT and four months of ADT [58]. Healthy was defined as no history of diabetes, congestive heart failure and coronary artery disease, or corrected (surgically or stented) coronary artery disease. At a median follow-up of 4.9 years, those receiving combined treatment had a 70 percent reduction in prostate cancer-specific mortality compared with those receiving brachytherapy only (HR 0.29, 95% CI 0.12-0.68). In another study of 5077 males treated with RT, neoadjuvant ADT was not associated with an increased risk of overall mortality in males with few or no comorbidities [59].
Two large randomized trials in patients with locally advanced prostate cancer demonstrated that RT plus ADT significantly decreases mortality due to prostate cancer and prolongs overall survival, although older males were underrepresented in these trials [60-62]. A study from the SEER-Medicare database analyzed cohorts of 8694 older males (age 76 to 85 years) with T2 or T3 disease and 2260 screen-detected males (age 65 to 85 years) with high-risk T1c disease (table 6) [63]. Although limited by the observational source of the data, these analyses demonstrated a significant improvement in overall and disease-specific survival for RT plus ADT compared with ADT alone; the magnitude of benefit was similar to that in the randomized trials after propensity matching for comorbidity and other risk factors. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Benefits of definitive treatment'.)
Side effects — Studies are conflicting as to whether or not age is an independent predictor of genitourinary and gastrointestinal side effects after RT. Some articles have found similar side effect profiles for older males undergoing RT compared with their younger counterparts [64-66], whereas others have found advanced age to be predictive of increased local side effects [67-69]. Studies have also suggested that males over the age of 70 develop toxicities more quickly [67]. Studies on brachytherapy have found that comorbid conditions are an important predictor of complications, along with age [70,71]. In an analysis of the SEER-Medicare database, a higher Charlson Comorbidity Index (table 5) and advanced age were both associated with increased urinary and bowel complications [70]. Another study of 528 males undergoing RT found functional outcomes to be affected by both age and comorbidity, especially diabetes [71]. (See "External beam radiation therapy for localized prostate cancer", section on 'Complications'.)
The use of ADT in combination with external beam RT has become the standard of care for males receiving RT for high- and intermediate-risk prostate cancer, based on improvements in cancer-specific and overall survival observed in multiple randomized trials. The optimal duration and timing (ie, starting before RT versus concurrently) are controversial areas. However, the role of ADT in combination with RT in older males needs to be carefully considered due to the higher rate of adverse events in this population. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Role of concurrent ADT' and "Side effects of androgen deprivation therapy".)
Post-treatment surveillance — The mainstay of post-treatment surveillance after definitive local therapy for prostate cancer is periodic assessment of serum PSA. Post-treatment surveillance for males who have received definitive local treatment for prostate cancer is discussed separately. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)
Androgen deprivation therapy — ADT alone has been used commonly as a primary treatment in older males, rather than definitive surgery or RT [20,23,26,48]. However, increasing data have raised concerns about this practice, and the use of ADT has declined [26]. These concerns are based on multiple studies suggesting increased mortality and shorter survival in patients given ADT as primary treatment; these studies are discussed separately. (See "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'Androgen deprivation therapy alone'.)
The American Urological Association (AUA) guidelines recommend that primary ADT not be included among the standard treatment options for males with localized prostate cancer unless for palliation of local symptoms in select patients with a limited life expectancy for whom definitive local therapy is not advised [72]. National Comprehensive Cancer Network (NCCN) guidelines also do not endorse primary ADT as a treatment option for males with clinically localized disease [73].
Guidelines from expert groups — The most extensive consensus-based recommendations for managing localized prostate cancer in older males are those of the SIOG, which have been updated several times [6-8]. The most recent version, which has been endorsed by the EAU and ESTRO [8], emphasizes a stepwise approach to the initial assessment of health status and life expectancy and also emphasizes early introduction of palliative care. (See 'Patient classification based on health status' above.)
Specific consensus-based recommendations for managing older males with localized prostate cancer from the EAU/ESTRO/SIOG are outlined in the table (table 11).
Advanced prostate cancer
Supportive care — Guidelines from both the EAU/ESTRO/SIOG and the American Society of Clinical Oncology (ASCO) emphasize the importance of early referral to palliative care, particularly for individuals with advanced cancer [8,74]. (See "Benefits, services, and models of subspecialty palliative care".)
For males with bone-metastatic castration-resistant prostate cancer (CRPC), osteoclast inhibition (with denosumab or a bisphosphonate) significantly decreases the rate of skeletal-related complications. These agents are not indicated in males with metastatic castration-sensitive prostate cancer given the lack of benefit in trials conducted in this setting. (See "Bone metastases in advanced prostate cancer: Management", section on 'Castration-resistant disease'.)
Castration-sensitive prostate cancer
ADT — The initial management of older males with newly diagnosed advanced prostate cancer is generally androgen deprivation therapy (ADT). (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)
The side effects of ADT are of particular concern in older males. (See "Side effects of androgen deprivation therapy".)
●ADT is associated with an increased risk of fractures [75,76], and these males have a higher likelihood of being osteopenic [77]. Males 70 years of age and older appear to be at greater risk of having decreased lean body mass compared with younger males treated with ADT [78].
●Endocrine changes occur with ADT, including a higher risk of developing metabolic syndrome and diabetes [79-83]. The prevalence of metabolic syndrome increases with age [84], indicating that older males started on ADT may either have or be at risk of developing or worsening aspects of metabolic syndrome.
●Males treated with ADT may be at a higher risk of developing coronary artery disease and all-cause mortality [85,86]. The relationship between coronary artery disease and treatment with ADT is discussed in detail separately. (See "Side effects of androgen deprivation therapy", section on 'Potential cardiovascular harm'.)
●Depressive, cognitive, and constitutional disorders occur more commonly in males receiving ADT [87,88].
●Sarcopenia and frailty are of general concern in older adults, and they may be exacerbated by ADT.
Although ADT is an important treatment for prostate cancer, the potential complications of such therapy and the interaction with existing comorbidities need to be considered on an individualized basis. In some cases that are associated with a slow natural history and low disease burden, surveillance alone may be indicated. (See "Side effects of androgen deprivation therapy".)
If ADT is chosen, consideration may be given to intermittent androgen deprivation (IAD), rather than continuous ADT, in older males in an attempt to decrease the side effect profile. However, the long-term impact of IAD on survival, the optimal timing, the triggers for initiation of additional treatment, and the populations that are candidates for IAD have not been defined. Furthermore, recovery of serum testosterone levels in males on ADT may be prolonged in older males. An expert panel from ASCO has concluded that the data are insufficient to support the use of IAD outside of a clinical trial [89,90]. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Intermittent versus continuous ADT'.)
ADT plus systemic therapy — ADT has been successfully combined with both docetaxel and abiraterone in males with newly diagnosed, very high-risk, non-metastatic, hormone-sensitive prostate cancer (ie, patients with stage T3 to T4 disease and a PSA >40 ng/mL, Gleason 8 to 10 disease, or else node-positive disease). (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Patients with low-risk/low-volume disease or not eligible for docetaxel'.)
The following results are available on ADT plus systemic therapy in males with newly diagnosed, metastatic, castration-sensitive prostate cancer:
●Males with newly diagnosed, metastatic, hormone-sensitive prostate cancer receiving docetaxel in addition to ADT experience significantly improved overall survival [91,92]. In the CHAARTED (Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) study, these benefits persisted in those over the age of 70 (HR 0.43, 95% CI 0.23-0.78) [91], although the difference was not significant in the STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) study (HR 0.90, 95% CI 0.64-1.26) [93].
●Similarly, overall survival was improved in those with metastatic hormone-sensitive prostate cancer receiving abiraterone in addition to ADT [94,95]. Of note, in the LATITUDE (Long-Acting Therapy to Improve Treatment Success in Daily Life) study of abiraterone, approximately 20 percent of males were over the age of 75. In this subset analysis, the effects were attenuated relative to younger males; the difference in overall survival was not statistically significant (HR 0.82, 95% CI 0.53-1.27), whereas radiographic progression-free survival remained statistically significant [94]. Similarly, in the STAMPEDE study of abiraterone, radiographic progression-free survival for males over the age of 70 was improved in those receiving abiraterone in addition to ADT, but the prostate cancer-specific mortality (HR 0.80, 95% CI 0.54-1.17) and overall survival (HR 0.94, 95% CI 0.69-1.29) were not statistically significant [95].
A pooled analysis of these three trials specifically examined the benefits of adding docetaxel or abiraterone to ADT in males older than 70 years with advanced castration-sensitive prostate cancer [96]. Although progression-free survival was significantly better with the addition of either docetaxel (HR 0.51, 95% CI 0.42-0.61) or abiraterone (HR 0.48, 95% CI 0.36-0.64), overall survival was not improved with either docetaxel (HR 0.86, 95% CI 0.69-1.07) or abiraterone (HR 0.85, 95% CI 0.67-1.08) in males over the age of 70.
These studies highlight the potential benefit of these combination therapies in older males while cautioning that uncertainty remains when considering the competing risks of mortality in such patients, reinforcing the importance of a geriatric assessment. Nevertheless, we agree with updated year 2019 consensus-based recommendations from the EAU/ESTRO/SIOG, which suggest ADT plus six cycles of docetaxel or abiraterone as a first-line treatment for fit older males with newly diagnosed, high-volume, castration-sensitive, metastatic prostate cancer (table 12) [8].
ADT plus docetaxel and a second systemic agent — For patients with metastatic castration-sensitive prostate cancer who are candidates for docetaxel, decision making about whether to add a second systemic agent to docetaxel plus ADT must be individualized and consider disease extent as well as functional and fitness status.
Two trials have demonstrated the superiority of adding a second systemic agent (darolutamide or abiraterone) to docetaxel plus ADT in metastatic castration-sensitive prostate cancer with high-risk/high-volume disease, while a survival benefit from the addition of enzalutamide could not be shown in a third trial. High-risk/high-volume disease in these trials was defined as the presence of visceral metastases and/or ≥4 bone metastases, including at least one outside the vertebral bodies and pelvis, or Gleason score ≥8 disease, or de novo metastatic disease at presentation.
This approach could be considered for older males who are sufficiently fit to tolerate combined treatment, as both trials enrolled older males:
●In the Arasens trial (darolutamide plus docetaxel and ADT), the age range included males 75 to 84 (16 percent of enrollees), and males 85 or older represented 0.5 percent of enrollees; they did not do subgroup analysis according to age at enrollment [97].
●In the PEACE-1 trial, patients were enrolled up to age 95; however, no subgroup analysis was performed according to age at enrollment [98].
These trials are described in more detail elsewhere. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'ADT plus docetaxel and a second systemic agent'.)
Prostate-directed therapy — For males with newly diagnosed metastatic prostate cancer, a low burden of bone metastases (defined as four or fewer bone metastases, with none outside the vertebral bodies or pelvis), and no visceral metastases, it is reasonable to pursue prostate RT in conjunction with systemic therapy, rather than systemic therapy alone. The pooled results of two trials (the HORRAD and STAMEDE trials) showed an overall improvement in biochemical progression-free survival (HR 0.74, 95% CI 0.67-0.82) and failure-free survival (HR 0.76, 95% CI 0.69-0.84) that translated into an approximately 10 percent benefit at three years [99]. There was an approximately 7 percent improvement in survival in males with fewer than five bone metastases. There was no evidence that the effect of prostate RT on survival varied in males ≤70 or older than 70 years. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer", section on 'Prostate-directed therapy'.)
Castration-resistant prostate cancer — In both fit and vulnerable patients, the best sequence of treatments for males who progress while receiving ADT (CRPC) is not known. Several options are available, and there are few trials comparing different strategies. An important point is that for most males, ADT should be continued as additional systemic therapy options are utilized sequentially. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Continuation of androgen deprivation therapy'.)
Non-metastatic castration-resistant prostate cancer — Three drugs are approved in the United States in this setting, based on studies including patients undergoing ADT who had a PSA doubling time ≤10 months, a PSA value >2 ng/mL, and no evidence of metastatic disease or nodal involvement:
●In the SPARTAN (Selective Prostate Androgen Receptor Targeting with ARN-509) trial of apalutamide (median age 74 years), there was an improvement in metastasis-free survival in males with a PSA doubling time <10 months, including those aged >75 years [100].
●Similar results were observed with enzalutamide in the PROSPER (Patient-Reported Outcomes following Enzalutamide or Placebo in Men with Non-metastatic, Castration-Resistant Prostate Cancer) trial (median age 74 years) [101].
●Similar benefits were shown with darolutamide in the ARAMIS (Androgen Receptor Antagonizing Agent for Metastasis-free Survival) trial [102].
Later analyses of all three trials also confirmed an overall survival benefit compared with placebo [103-105]. In this setting, the efficacies of these three agents have not been compared directly, but they appear to be similar. Differences in the safety profiles may drive the choice of one treatment over another. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway", section on 'Enzalutamide'.)
The metastasis-free survival and overall survival benefits of all three agents in males over age 80 with nonmetastatic CRPC have also been shown in a pooled analysis [106] of patient level data from all three randomized trials [100-102]. However, the analysis also revealed that grade 3 or worse adverse events with androgen signaling inhibitors were reported in a higher percentage of males over age 80 (55 versus 41 percent with placebo) as compared with younger individuals (44 percent versus 30 percent with placebo). The most common of these events were hypertension and bone fracture.
Metastatic castration-resistant prostate cancer — Docetaxel was the first agent that was demonstrated to improve survival in CRPC. More recently, several additional agents (ie, abiraterone, enzalutamide, sipuleucel-T, radium-223, cabazitaxel) have been shown to improve survival and offer additional options for males with castration-resistant disease. Several of the pivotal studies using these newer agents included a significant proportion of older males, with similar improved survival compared with younger males. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
●Androgen pathway interference – Both abiraterone and enzalutamide have demonstrated improved survival in chemotherapy-naïve males with asymptomatic or minimally symptomatic disease [107,108], as well as in those who had previously received docetaxel [109,110]. The effects were similar in subset analyses of males over the age of 75. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Interference with androgenic stimulation' and "Castration-resistant prostate cancer: Treatments targeting the androgen pathway".)
For frail patients or those who are not candidates for docetaxel, use of abiraterone or enzalutamide is an option. Even in the post-docetaxel setting, the response rates for abiraterone and enzalutamide have been similar in older and younger males, with similar overall adverse events, although specific complications were higher in older males in the abiraterone (atrial fibrillation and tachycardia) and enzalutamide (peripheral edema, fatigue, and diarrhea) studies [111,112]. Of note, 85 percent of the males in these studies had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
●Chemotherapy
•Healthy/fit males – Healthy males should be offered standard chemotherapy. However, in an analysis of SEER-Medicare data through 2004, the majority of older males with metastatic prostate cancer did not receive chemotherapy [113]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Chemotherapy-naïve patients'.)
•Vulnerable males – Vulnerable males may be able to receive standard chemotherapy after correction/treatment of a specific reversible impairment if one is identified [8].
-Docetaxel – The standard chemotherapy regimen for CRPC is docetaxel (75 mg/m2 every three weeks) with prednisone. Subset analyses of the trials establishing the role of this approach have shown that older males, including those ≥75 years, responded as well as younger patients [114,115]. However, the challenges of using docetaxel in older individuals are well recognized [116]. In one study, treatment with docetaxel plus prednisone was not feasible in males aged 75 and older who were considered vulnerable or frail [117].
Because of concerns about myelosuppression and other adverse effects of chemotherapy in older patients [118], studies have explored lower dosing of docetaxel (30 mg/m2 weekly) [116,119-121]. Results have suggested that this dosing may be effective against cancer progression, with a lower rate of myelosuppression, although with no improvement in overall survival. However, a review of patients treated with either three-week (n = 96) or weekly (n = 80) docetaxel found that there was a greater percentage of dropouts with the weekly regimen compared with the three-week schedule (30 versus 8 percent) [116].
If docetaxel is used in older males, we typically start with a lower dose (60 or 65 mg/m2) every three weeks.
-Cabazitaxel – Cabazitaxel is a taxane derivative that has been shown to prolong survival compared with mitoxantrone in patients who have progressed on docetaxel [122,123]. The improvement in survival was not affected by age. The CARD trial also showed improved outcomes with cabazitaxel versus abiraterone/enzalutamide in males progressing after prior docetaxel and the alternative agent (abiraterone or enzalutamide); benefits were similar in older males although with more treatment-emergent adverse effects compared with abiraterone/enzalutamide [124]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Men who have received prior docetaxel'.)
Cabazitaxel is associated with less neuropathy than docetaxel, and it is the preferred taxane for older males with preexisting neuropathy who are docetaxel-naïve. There are at least two studies of modified schedules of cabazitaxel that might be associated with a more favorable toxicity profile in older males [125,126].
•Frail males – The role of chemotherapy in frail males (ie, those with an irreversible impairment) is less certain; an adapted treatment regimen may be considered. Chemotherapy is generally not indicated in males with terminal illness, and treatment is symptomatic.
●Radium-223 – Another therapeutic option for males without visceral metastases is radium-223, which has been shown to decrease the incidence of skeletal-related events and prolong overall survival in males with widely disseminated bone metastases [6,127]. In the phase III trial demonstrating the safety and efficacy of this agent, the median age of the patients was 71 years. (See "Bone metastases in advanced prostate cancer: Management", section on 'Radium-223'.)
●Immunotherapy – Sipuleucel-T, a dendritic cell vaccine that is prepared from peripheral blood mononuclear cells obtained by leukapheresis, has been shown to prolong overall survival in males with minimally symptomatic, metastatic CRPC. There was no difference in the effects in older versus younger patients [128]. (See "Immunotherapy for castration-resistant prostate cancer", section on 'Therapeutic vaccination with Sipuleucel-T'.)
In May 2017, the US Food and Drug Administration (FDA) approved the immune checkpoint inhibitor pembrolizumab for treatment of a variety of advanced solid tumors (including prostate adenocarcinoma) that have high levels of microsatellite instability (MSI-H) or are deficient in mismatch repair (dMMR), that progressed following prior treatment, and for which there are no satisfactory alternative treatment options. (See "Immunotherapy for castration-resistant prostate cancer", section on 'PD-1 pathway inhibition'.)
Surveillance during treatment — Surveillance strategies during treatment for advanced prostate cancer are discussed separately. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)", section on 'Assessment during treatment'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of prostate cancer".)
SUMMARY AND RECOMMENDATIONS
●The management of prostate cancer in older males requires careful assessment of multiple factors, including comorbidities, dependency, activities of daily living, and nutritional status, which ultimately are more important than chronologic age. Based on a detailed assessment of these parameters (table 1), patients should be categorized as fit, vulnerable, or frail (algorithm 1). Vulnerable or frail patients should undergo a comprehensive geriatric assessment. (See 'Patient classification based on health status' above and "Comprehensive geriatric assessment for patients with cancer".)
●For males with localized prostate cancer, the choice of treatment depends on the assessment of the patient's overall status, his estimated life expectancy, as well as the risk stratification of his primary tumor (table 11). (See 'Localized disease' above.)
•Healthy older males should have the same range of potentially curative treatment options as younger patients, including radical prostatectomy and radiation therapy (RT; external beam and/or brachytherapy); active surveillance is an appropriate option for many patients with very low- and low-risk disease and for some males with favorable intermediate-risk disease.
•Vulnerable patients with a reversible problem who have high-risk localized prostate cancer generally should receive the same definitive treatment as younger patients, following appropriate management of their other underlying problems. For individuals with low-/intermediate-risk localized prostate cancer, active surveillance or watchful waiting is generally preferred.
•Frail older males with an irreversible problem should generally receive symptomatic/palliative management without definitive treatment (eg, initial hormone therapy).
●Early referral to palliative care is encouraged for older males with prostate cancer, particularly in the setting of advanced castration-resistant disease. (See 'Supportive care' above.)
●Patients with advanced prostate cancer are managed initially with androgen deprivation therapy (ADT). Particular attention should be paid to the complications of ADT and the potential interactions with underlying comorbidities (table 12). (See 'Castration-sensitive prostate cancer' above and "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer" and "Side effects of androgen deprivation therapy".)
●The addition of docetaxel or abiraterone to ADT is a reasonable first-line treatment for fit older males with newly diagnosed, high-volume, castration-sensitive, metastatic disease. Given the uncertainty of benefit when considering the competing risks of mortality in such patients, a geriatric assessment should be undertaken in these individuals. (See 'ADT plus systemic therapy' above.)
●For individuals who are candidates for docetaxel, decision making about whether to add a second systemic agent to docetaxel plus ADT must be individualized and consider disease extent as well as functional and fitness status. (See 'ADT plus docetaxel and a second systemic agent' above.).
●For males with newly diagnosed metastatic disease, a low burden of bone metastases (defined as four or fewer bone metastases, with none outside the vertebral bodies or pelvis), and no visceral metastases, it is reasonable to pursue prostate RT in conjunction with systemic therapy, rather than systemic therapy alone. (See 'Prostate-directed therapy' above.)
●Males with a rising prostate-specific antigen (PSA) after ADT who have a PSA doubling time ≤10 months, a PSA value >2 ng/mL, and no evidence of metastatic disease or nodal involvement are appropriate candidates for apalutamide, enzalutamide, or darolutamide. (See 'Non-metastatic castration-resistant prostate cancer' above.)
●Males with metastatic castration-resistant prostate cancer can be candidates for the same therapies as younger patients, including chemotherapy (docetaxel, cabazitaxel), abiraterone, enzalutamide, apalutamide, radium-223, and sipuleucel-T. The choice and sequence of therapy should incorporate information about the overall clinical status of the patient. Abiraterone and enzalutamide are appropriate options for older males who are not candidates for chemotherapy. (See "Overview of the treatment of castration-resistant prostate cancer (CRPC)".)
ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.
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