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The burden of metastatic prostate cancer to society is enormous, both in terms of health care resources and human suffering; thus, the implementation of knowledge derived from quality clinical trials to community practice is imperative (1). Prostate cancer continues to be the most frequently diagnosed non-cutaneous cancer in American men and the second leading cause of cancer-related death (1), suggesting a critical need for improved screening and early diagnosis at a curable stage, and enhanced efficacy of therapy for advanced metastatic disease. Following the US Preventive Services Task Force (USPSTF) report in 2012 (2), there was a significantly reduced utilization of prostate cancer screening with prostate-specific antigen (PSA) testing, resulting in a lower overall detection of prostate cancer, but an unfortunate increase has emerged in the proportion of men presenting at advanced stages (1, 3–5). For example, recent data show a significant 41% increase in metastatic prostate cancer from 2010 to 2018 in men aged 45 –75 (3). This report focuses upon the treatments provided to the subgroup of men presenting with de novo metastatic disease in the real-world setting.

For decades, suppression of testosterone by castration or androgen deprivation therapy (ADT) has been the cornerstone of life-prolonging therapy for metastatic prostate cancer (6) and continues to improve with newer agents targeting specific components of the androgen signaling pathway (7–9). Yet, metastatic disease is essentially incurable, and mortality is nearly 70% by 5 years after diagnosis (10–13). Sadly, the median survival for men with castrate-resistant prostate cancer (CRPC) ranges from 18 to 24 months in most studies (12, 14, 15). Cytotoxic chemotherapy emerged as a beneficial treatment modality for metastatic CRPC, initially in the management of pain with mitoxantrone (16) and subsequently with docetaxel prolonging survival in landmark phase III trials by 2004 (17, 18) and supported by subsequent studies (19, 20). Soon thereafter, cabazitaxel, a second-generation taxane, showed a survival benefit in docetaxel refractory CRPC (21). With success in CRPC in the metastatic setting, the potential of adding taxane chemotherapy to androgen deprivation therapy (ADT) for men who present at initial diagnosis with treatment-naive metastatic disease was investigated in studies demonstrating improved overall survival and improved secondary endpoints such as prostate−specific antigen (PSA) failure and time to recurrence, particularly for those with higher volume disease (10, 11, 22, 23). National Comprehensive Cancer Network (NCCN) guidelines recommend ADT with docetaxel for six cycles as one of several options for the initial treatment of castration-naive metastatic prostate adenocarcinoma and was first included in the 2014 update (10, 24).

Our objective is to assess how the studies of chemotherapy combined with hormone therapy over recent decades have translated into real-world clinical practice for men with a new diagnosis of metastatic prostate cancer. The present study provides a comprehensive and contemporary (2004 –2018) summary of the large Surveillance, Epidemiology, and End Results (SEER) database. We also report the impact of initial chemotherapy on survival based upon the histopathological subtype and a number of relevant clinical and demographic factors.

The SEER 18 database, capturing approximately 28% of the total United States population, provides a valuable resource to assess patterns of care for prostate cancer. We specifically examined the utilization of systemic cytotoxic chemotherapy for men with metastatic disease at an initial diagnosis from 2004 to 2018, a period when results of clinical trials suggested new strategies for care. As expected, few men not showing metastatic disease received initial chemotherapy throughout the period. During 2004–2013, the proportion of patients with de novo metastatic adenocarcinoma receiving chemotherapy was low (5.8%) but significantly increased to an average of 21.4% during 2014 –2018. The pattern observed likely represents a shared decision- making process (27) between the patient and provider throughout the interval (2004–2018) with utilization of chemotherapy increasingly being offered as an option following publication of new clinical trial results approximately 2014 (10, 11, 22, 23). By 2014, National Comprehensive Cancer Network (NCCN) guidelines recommended ADT plus docetaxel for six cycles as one of several options for the initial treatment of castration- naive metastatic prostate adenocarcinoma (24). Multivariate survival analysis of data from 2004 to 2013 showed that chemotherapy in men with distant metastasis was associated with worse cancer-specific and overall survival; by contrast, it was associated with improved prognosis during 2014–2018.

This is most likely related to patient selection, with chemotherapy being used for men with the most ominous presentation. In contrast to adenocarcinoma, men with neuroendocrine prostate carcinoma (0.1% of all prostate cancer) show an average of 54% of patients receiving chemotherapy with no clear directional change over the entire period. Interestingly, chemotherapy was associated with improved cancer-specific and overall survival in neuroendocrine carcinoma patients during 2014–2018 but not during 2004–2013, perhaps due to improvements in supportive care and patient selection.

For decades, studies of cytotoxic chemotherapy failed to demonstrate benefits for men with metastatic prostate cancer due to challenges in objectively measuring response for a disease dominated by nodal and bone metastasis coupled with a lack of efficacy (28–30). The approval of mitoxantrone for pain control established chemotherapy as an option for men with advanced metastatic disease in 1999 (16, 31). By 2004, a landmark series of studies showed that docetaxel-based therapy for the first time demonstrated improved survival for men with metastatic- castration-resistant prostate adenocarcinoma (17, 18, 31). Newer studies refined our knowledge and documented benefits dependent upon dose intensity (32) and that taxane analogues may prolong benefits (21). Such progress led investigators to consider moving docetaxel chemotherapy into initial treatment strategies for newly diagnosed hormone-sensitive metastatic prostate cancer. Trials showing improved biochemical progression-free survival with the addition of docetaxel to ADT in metastatic hormone-naive prostate cancer patients were emerging by 2013 (23), and by 2015, studies were showing that upfront docetaxel chemotherapy improved overall survival, failure-free survival, and progression-free survival (10, 22, 23). Our study examines how this knowledge impacted therapy for prostate cancer patients in the non-protocol standard practice over the time frame that these results became available (33).

As expected, our study revealed that chemotherapy for those with metastatic adenocarcinoma at diagnosis was sparingly employed at 5.8% prior to 2014 followed by a dramatic rise to nearly 30% from 2014 to 2016. The rapid change was certainly driven by the enthusiasm derived from the new studies and guidelines (23). Although it is possible that the wider insurance coverage becoming available at this time resulting from the American Afford Care Act (34) contributed somewhat, we suspect that the main driving force of adoption was the published research and NCCN guidelines. Yet, it may be surprising to some that only 20%–30% are receiving upfront chemotherapy after 2013–2014. We suspect that both providers and patients contribute to these findings. Our analysis indicates that practitioners are using a range of criteria in patient selection for early chemotherapy, which of course is then modulated by patient preferences after considering risks and benefits. Men receiving initial chemotherapy are younger, typically married (perhaps a marker of support systems), with more advanced T stage, higher Gleason score, positive lymph node metastasis, and more advanced M staging. Thus, it is likely that patients perceived to have a more aggressive phenotype based upon established risk factors are more likely to be offered chemotherapy by practitioners. Of course, we do not have data regarding the initial discussion of options for these men and what percentage were offered chemotherapy and declined. One additional factor may be referral patterns with the urologist typically serving as the initial focal point for diagnosis and perhaps not having medical oncology engaged at the time of the initial treatment plan. Clearly, with only 30% of men receiving chemotherapy, the perceived benefits do not exceed risks in the minds of practitioners and or patients.

Interestingly, we found that from 2004 to 2013, the administration of chemotherapy was associated with worse prognosis compared with no chemotherapy. As chemotherapy became more widespread, we observed a significantly improved cancer- specific and overall survival during 2014–2018. Notably, these findings are verified in subsequent propensity score matching analyses. The poorer outcomes in 2004–2013 likely represents the use of initial chemotherapy for men with greater cancer volume and more aggressive disease, a subgroup destined to have a shorter life expectancy. The lack of a standard of care chemotherapy regimen (agents, dose, and duration) for de novo distant metastatic patients may also attribute to the worse outcome during the period. Multiple factors, such as cancer grade, distribution of lesions and volume of disease, PSA, age, and other variables impact offering the chemotherapy option. A previous publication, employing an older version of SEER database (2014–2015) with far less data, also found that chemotherapy-exposed prostate cancer patients exhibited significantly better overall survival (HR=0.82, 95% CI: 0.72–0.96, p=0.01) compared to their chemotherapy- naive counterparts (35). The finding was confirmed in propensity score matching analyses (multivariable HR: 0.77, 95% CI: 0.66-0.90, p<0.001) (35). Utilizing a large national cancer database in the United States (2014–2015), another retrospective cohort study revealed that upfront chemotherapy was associated with longer overall survival (HR= 0.78, 95% CI: 68–0.89, p < 0.001) in men with de novo, treatment- naive metastatic prostate cancer after adjusting for patient and clinical variables (36).

Due to lack of precise data in the SEER database regarding lesion numbers, size, and locations of metastasis, it is not possible to precisely define the high-volume disease. Our multivariate survival analysis suggests that chemotherapy displayed a more beneficial impact for men with potentially higher volume. Men with the nodal metastasis experience no benefit, whereas those with bone metastasis fare better with chemotherapy, and the greatest benefit is seen in men with the visceral disease with or without bone and nodal metastasis.

Not surprisingly, age is shown to be a risk factor for death and particularly strong over the age of 80 years. This and other studies suggest that chemotherapy is less often prescribed for older patients with metastatic prostate cancers (37, 38) and likely due perceived risks associated with frailty, accumulating comorbidities, and poor resilience. Interestingly, we find the benefit of chemotherapy to be best in the ages of 70 –80 years, both on cancer- specific and overall survival. Those younger than 70 and older than 80 tended to gain little or no benefit from chemotherapy. Perhaps, younger men with de novo metastatic prostate cancer have a more aggressive disease that is less sensitive to therapy, while older men have comorbidities impacting resilience and tolerability. Similar to our finding, another report suggests that chemotherapy plus ADT, compared to ADT alone, was associated with improved overall survival in de novo metastatic prostate cancer patients ≥70 years but not in patients <70 years (39).

Our multivariate survival analyses quantitate the impact of several relevant variables on survival in this cohort. We have limited data on the impact of integrating radiotherapy and surgery but do see a worse outcome noted for those receiving both. It is possible that men with significant and symptomatic local disease have a more aggressive phenotype or medical complications that impact survival. We see a clear trend for married men doing better in survival, perhaps a marker for stronger support systems and compliance with care plans. We did not detect a difference in response based on black vs. white race, but the Southern region of the United States consistently shows poorer survival than the Midwest, with the West and Northeast being similar, perhaps reflecting the impact of social and economic issues on health care access and quality (40, 41). Higher grade cancers and greater disease burden, as indicated by PSA, TNM staging, and Gleason scoring, were strongly related to poor outcomes for those presenting with de novo metastatic adenocarcinoma.

Neuroendocrine carcinoma is the rare histological type of prostate cancer with the worst prognosis (25, 42). The disease is typically defined histopathologically and often characterized by lower PSA secretion, higher risk of metastasis, an inferior response to ADT, and poor prognosis (26, 43–45). Small early studies supported the use of chemotherapy with agents often used for cancers of other tissue origins with neuroendocrine features (46). Chemotherapy, radiotherapy, or combinations are associated with improved overall survival compared with palliative therapy (47). We observe that an average of 54% of patients with neuroendocrine prostate cancer are treated with first-line chemotherapy and is steady from 2004 to 2018. Chemotherapy is associated with improved cancer-specific and overall survival during 2014–2018, but not during 2004–2013, perhaps due to improved supportive care plans and better patient selection. Hence, our findings may support the use of chemotherapy for both de novo and treatment-emergent neuroendocrine prostate cancer due to the potential survival benefits.

This retrospective study has limitations. Our study is subject to the constraints of the SEER database, including the precision of data collection and the number of variables collected. There is a lack of information on the specific chemotherapy regime, dose of drug, compliance, and dose intensity including the number of cycles. The database has no information on concurrent ADT and the types or duration of agents provided. Indeed, we suspect that the increased use of effective agents impacting androgen receptor signaling may reduce the frequency of selecting taxane-based chemotherapy in the up-front approach to de novo metastatic disease since 2016 (Figure 1). There is no information on other important outcomes such as toxicities of chemotherapy, quality of life, recurrence of cancer and additional therapy, and the dynamic change in PSA. Our study is limited by the inherent challenges of a retrospective cohort design. For example, it is likely that patients with better performance status were selected for chemotherapy, which may contribute to better survival outcomes. Hence, selection bias is inevitable but is clearly a component of practice decisions. The strength of this study is the very large sample size providing accurate insight into practice patterns in a real world setting during a period when new data were emerging.

Chemotherapy has been increasingly employed in the community for men with de novo metastatic adenocarcinoma at diagnosis following a series of publications in 2013–2014, yet for less than one-third of men. Our data suggest that both medical practitioners and patients may be carefully considering the risks and benefits for each individual based upon age, histopathological features, PSA, staging criteria, comorbidities, and a number of factors such as overall performance status. Findings of this study support the initial treatment with chemotherapy in men in the 70–80 age group presenting de novo with more aggressive features or greater volume of metastatic disease. Clearly, our work suggests that shared decision making is the strategy in the community for men presenting with metastatic adenocarcinoma who are mostly seniors and often with comorbidities. In contrast, the treatment of neuroendocrine prostate cancer with initial chemotherapy has been stable at approximately 50%, but with improving outcomes in recent years.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Concept and design: SW and SC. Data acquisition and analysis: SW and SC. Interpretation of data: all authors. Drafting of the manuscript: SW and SC. Critical revision of the manuscript for important intellectual content: all authors. Supervision: SC. All authors contributed to the article and approved the submitted version.