Advertisement

Sites of synchronous distant metastases and prognosis in prostate cancer patients with bone metastases at initial diagnosis: a population-based study of 16,643 patients

  • Feng ZhaoEmail author
  • Jili Wang
  • Meiqin Chen
  • Danni Chen
  • Sunyi Ye
  • Xinke Li
  • Xin Chen
  • Guoping RenEmail author
  • Senxiang YanEmail author
Open Access
Research
Part of the following topical collections:
  1. Clinical Genomics

Abstract

Background

Bone is a preferential site for prostate cancer (PCa) metastasis. However, sites of synchronous distant metastases in PCa patients with bone metastases at initial diagnosis and their impacts on prognosis are still unclear, limiting our ability to better stratify and treat the patients. In this study, we examined the sites of synchronous extra-skeletal metastases in de novo PCa patients with bone metastases and their associated prognoses.

Methods

In total, 16,643 de novo PCa patients with bone metastases from the SEER database were included. After stratification of metastatic sites (bone, lung, liver, and brain) and treatment modalities, overall survival (OS) and independent predictors of OS, were analyzed.

Results

Lung was the most frequent site of synchronous metastases, followed by liver, while brain metastases were relatively uncommon. Patients with bone-only metastases showed the longest mean survival time (35.87 months, p < 0.001), followed by patients with bone and lung metastases (30.74 months, p < 0.001). Patients with bone and liver metastases had the shortest mean survival time (17.39 months, p < 0.001). Age > 70 years, unmarried status, high tumor grade, prostate-specific antigen (PSA) > 50 ng/ml, and Gleason score ≥ 8 were associated with poor OS (all p < 0.01). Asian or Pacific Islander ethnic background was associated with a favorable OS (all p < 0.01). Chemotherapy improved OS in patients without brain metastases (all p < 0.05). For patients with bone-only metastases, radical prostatectomy (RP) (HR, 0.339; 95% CI 0.231–0.495; p < 0.001), brachytherapy (BT) (HR, 0.567; 95% CI 0.388–0.829; p = 0.003), and chemotherapy (HR, 0.850; 95% CI 0.781–0.924; p < 0.001) were associated with prolonged OS.

Conclusions

Age, race, tumor grade, PSA, Gleason score, sites of synchronous extra-skeletal metastases, as well as treatment modalities affected OS in newly diagnosed PCa patients with bone metastases. Synchronous liver metastases were associated with poor OS. Chemotherapy improved OS in patients without brain metastases. RP and BT improved OS in patients with bone-only metastases. Further investigation is warranted to validate these findings.

Keywords

Prostate cancer Metastasis Surgery Radiotherapy (RT) Chemotherapy Overall survival (OS) Prognosis 

Abbreviations

ADT

androgen deprivation therapy

BT

brachytherapy

CHAARTED

Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer

EAU

European Association of Urology

EBRT

external-beam radiation

NCCN

National Comprehensive Cancer Network

OS

overall survival

PCa

prostate cancer

PSA

prostate-specific antigen

RP

radical prostatectomy

RT

radiotherapy

SEER

Surveillance, Epidemiology, and End Results

Background

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men, with an estimated 1.1 million diagnoses worldwide in 2012, accounting for 15% of all diagnosed cancers [1, 2]. Approximately 1.7–11.9% of patients have bone metastases at initial diagnosis, and the incidence varies greatly in different countries or regions, which may attribute to the adoption of different prostate-specific antigen (PSA) screening policies [3, 4, 5]. The bone is the most common distant metastatic site of PCa and many existing literatures have focused on the topic and reported the prognosis of this subgroup of PCa patients [5, 6, 7]. For example, Norgaard et al. [4] reported that the 1-year and 5-year survival rates were approximately 47% and 3%, respectively, for PCa patients with bone metastases at initial diagnosis. Apart from PCa, breast and kidney cancers also have a propensity of metastasizing to the bones; and patients with disease that remains confined to the skeleton have a better prognosis than do those with synchronous multiple sites of involvement [8, 9]. However, the sites of synchronous extra-skeletal metastases, e.g., the lung, brain, and liver, and the associated prognostic outcomes in de novo PCa patients with bone metastases have not been thoroughly investigated.

With regard to treatment, androgen deprivation therapy (ADT) has been the backbone of treatment in de novo PCa patients with bone metastases. Recently, ADT plus chemotherapy (docetaxel) or abiraterone acetate are also recommended as first-line treatment options for metastatic PCa patients [10, 11]. Most recently, the European Association of Urology (EAU) 2019 and National Comprehensive Cancer Network (NCCN) 2019 V2 clinical practice guidelines recommended that ADT combined with prostate radiotherapy (RT) be offered to patients who first present with a low volume metastasis (M1) according to the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) criteria and STAMPEDE phase 3 randomized trial, which randomized 2061 patients based on the mean duration to standard systemic therapy with or without radiotherapy to the primary tumor [10, 11]. However, until now, local definitive surgery has not been a part of the treatment recommendation for newly diagnosed PCa with bone metastases, although some studies have suggested that local resection of the primary cancer might be beneficial to prolonging the survival rate of patients [12, 13, 14].

Therefore, the primary objective of this study was to investigate the sites of synchronous distant metastases of other organs (lung, brain, and liver) and the associated prognoses in de novo PCa patients with bone metastases, using data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. The secondary aim was to investigate the survival benefits of surgery, RT, and chemotherapy in patients through the stratification of metastatic sites and treatment modalities.

Patients and methods

Study population

The SEER database of the National Cancer Institute was used for this analysis. The SEER program, which consists of 18 population-based cancer registries (released in November 2018) and covers approximately 26% of the sample of the United States population, is representative of the United States in terms of demographics, tumor, diagnostics and treatment characteristics.

PCa patients diagnosed between 2010 and 2016 were selected from the database. The eligibility criteria included the following: (1) distant metastases (M1 for patients diagnosed between 2010 and 2015 (the 7th AJCC M stage), cM1 or pM1 for patients diagnosed in 2016 (derived-SEER combined M stage)); (2) tumor sequence number labeled “one primary only”; (3) bone metastases; and (4) survival information available. Finally, a total of 16,643 eligible patients were included in this study (Fig. 1).
Fig. 1

This flow chart describes the steps taken to identify cases in the SEER database of de novo primary prostate cancer patients with bone metastases

Variable definitions

Patient demographic variables, including age at diagnosis, marital status, and race, were extracted from the database. There are 6 marital statuses in the SEER database: married, single, widowed, divorced, separated and unmarried or domestic partner. Only “married” patients were included in the married cohort. Others such as “single”, “divorced”, “widowed”, “separated” or “unmarried or domestic partner” were categorized as “unmarried”. Tumor factors, including tumor grade, serum PSA, Gleason Score, and metastatic site (bone, brain, liver, and lung), as well as treatment modalities, such as surgery, radiotherapy, and chemotherapy, were obtained from the database. Furthermore, surgery was also subcategorized as endoscopic therapy (surgery site codes 10–30) and radical prostatectomy (RP) (surgery site codes 50 or 70), while radiotherapy was subclassified as brachytherapy (BT) (radiation-specific codes 2, 3, or 4) and external-beam radiation (EBRT) (radiation-specific code 1). Additionally, the overall survival (OS) status and information on the months (M) of survival were collected for survival analysis.

Statistical analyses

Categorical variables are reported as counts (percentages). PCa patients with bone metastases were classified according to the sites of metastases (bone-only, bone and lung, bone and liver, bone and brain, and bone metastases and ≥ 2 other sites). Kaplan–Meier analysis and log-rank tests were used to estimate the survival times of patients. Landmark analysis was performed when survival curves cross each other. Univariable and multivariable Cox proportional hazards models were used to analyze the associations of patient characteristics, the sites of metastases and treatment modalities with patient survival. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. Statistical analyses were performed with SPSS version 25.0 (SPSS Inc., Chicago, IL, USA) and EmpowerStats statistical software (http://www.empowerstats.com/). A p value < 0.05 was considered statistically significant. Forest plots were generated using the forestplot package in R software (version 3.5.3).

Results

The demographic and clinicopathological characteristics of the patients are summarized in Table 1. The median age was 71 years old. Most patients (74.3%) were White, and more than half of the patients (54.0%) were married. The majority of patients (90.56%) with available tumor grade information had poorly differentiated diseases. For the patients with available PSA information, most (69.44%) had PSA > 50 ng/ml. For the patients with available Gleason information, the majority (83.08%) had Gleason scores of 8–10. A minority of patients with bone metastasis had concomitant lung metastases (5.9%), liver metastasis (2.5%), brain metastasis (0.8%), and 2 or more other sites (brain, liver, and lung) of metastases (1.3%). Patient with bone metastases received treatment modalities including surgery (9.6%), RT (22.6%), and chemotherapy (13.3%).
Table 1

Patient demographics and clinical characteristics of de novo prostate cancer patients with bone metastases (N = 16,643)

Characteristics

Level

Number (%)

Age at diagnosis

Mean ± SD

71.41 ± 11.318

Median (range)

71 (34–105)

≤ 70

8079 (48.5%)

> 70

8564 (51.5%)

Race

White

12,367 (74.3%)

Black

303 (18.2%)

Asian or Pacific Islander

989 (5.9%)

Others/unknown

257 (1.5%)

Marital status

Married

8987 (54.0%)

Unmarried

6542 (39.3%)

Unknown

1114 (6.7%)

Tumor grade

Well differentiated

96 (0.6%)

Moderately differentiated

861 (5.2%)

Poorly differentiated

9097 (54.6%)

Undifferentiated

87 (0.5%)

Unknown

6502 (39.1%)

PSA

≤ 10 ng/ml

1271 (7.6%)

10–20 ng/ml

1240 (7.4%)

20–50 ng/ml

2037 (12.2%)

> 50 ng/ml

10,336 (62.1%)

Unknown

1759 (10.6%)

Gleason

≤ 6

219 (1.3%)

3 + 4

536 (3.2%)

4 + 3

885 (5.3%)

8–10

8052 (48.4%)

Unknown

6951 (41.8%)

Metastatic sites

Bone-only

14,872 (89.4%)

Bone and lung

976 (5.9%)

Bone and liver

414 (2.5%)

Bone and brain

126 (0.8%)

Bone and ≥ 2 other sites

255 (1.3%)

Surgery

Yes

1593 (9.6%)

No/unknown

15,085 (90.4%)

Radiotherapy

Yes

3765 (22.6%)

No/unknown

12,878 (77.4%)

Chemotherapy

Yes

2216 (13.3%)

No/unknown

14,427 (86.7%)

PSA prostate specific antigen

As shown in Table 2 and Fig. 2, patients with bone-only metastases showed the longest mean survival time (35.87 months, all p < 0.001), followed by bone and lung metastases (30.74 months, all p < 0.001). Patients with bone and liver metastases had the shortest mean survival time (17.39 months, p < 0.001). The risks of mortality for PCa patients with different types of metastases are illustrated in Fig. 3. Specifically, as shown in Fig. 3, older age (age > 70 years), an unmarried status, high tumor grade, PSA > 50 ng/ml, and Gleason score ≥ 8 were associated with a worse OS (all p < 0.01), whereas an Asian or Pacific Islander ethnic background was associated with a better OS (p < 0.001). As to treatment modalities, only chemotherapy reduced the risk of death (HR, 0.848; 95% CI 0.786–0.914; p < 0.001). Both surgery (HR, 1.006; 95% CI 0.932–1.086; p = 0.875) and RT (HR, 0.955; 95% CI 0.907–1.005; p = 0.079) had little effect on survival.
Table 2

Accumulated overall survival (OS) rates (median, mean, 1-, 2-, and 5-year) of de novo prostate cancer patients with bone metastases

Metastatic sites

Median survival (months)

Mean survival (months)

1-year (%)

2-year (%)

5-year (%)

Bone-only

27

35.87

73.6

53.4

24.2

Bone and lung

20

30.74

63.2

44.6

22.1

Bone and liver

10

17.39

44.5

22.6

5.1

Bone and brain

10

19.11

42.0

23.9

11.8

Bone and ≥ 2 other sites

11

20.23

45.5

26.4

11.4

Fig. 2

Kaplan-Meier survival curves and log-rank tests showing that overall survival (OS) differences between prostate cancer patients with bone-only metastases, bone and lung metastases, bone and liver metastases, bone and brain metastases, and bone and ≥ 2 other sites metastases (i.e., bone-only vs bone and lung, bone-only vs bone and liver, bone-only vs bone and brain, and bone-only vs bone and ≥ 2 other sites, all p < 0.001; bone and lung vs bone and liver, bone and lung vs bone and brain, bone and lung vs bone and ≥ 2 other sites, all p < 0.001; bone and liver, bone and brain, and bone and ≥ 2 other sites, compared with each other, all p > 0.05)

Fig. 3

Multivariable Cox proportional hazards models were used to analyze associations of patients’ characteristics, sites of metastases and treatment modalities against survival in de novo PCa patients with bone metastases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated and summarized with forest plots

The HRs and 95% CIs of the overall mortality for patients are summarized in Table 3, according to the stratification of metastatic sites and treatment modalities. Chemotherapy improved OS in patients with bone-only metastases (HR, 0.850; 95% CI 0.781–0.924; p < 0.001), bone and lung metastases (HR, 0.737; 95% CI 0.552–0.984; p = 0.039), and bone and liver metastases (HR, 0.651; 95% CI 0.491–0.864; p = 0.003). To better understand the contribution of surgery and RT to OS, we subclassified the surgical treatment as radical surgery (RP), endoscopic therapy and no/unknown surgery and subdivided RT into BT, EBRT and no/unknown RT for further analysis. For the patients with bone-only metastases, RP (HR, 0.339; 95% CI 0.231–0.495; p < 0.001) and BT (HR, 0.567; 95% CI 0.388–0.829; p = 0.003) significantly prolonged OS, while endoscopic therapy was associated with a worse OS. EBRT had no effect on OS. The Kaplan–Meier OS curves for the patients with bone-only metastases are shown in Fig. 4, which revealed that patients who received RP had a significantly longer OS than those underwent endoscopic therapy and no/unknown surgery. Patients who received BT had a significantly longer OS than those underwent EBRT and no/unknown RT. Interestingly, stratified by chemotherapy, Fig. 4c showed the Kaplan–Meier survival curves cross each other at point of 35 months. Thus, landmark analysis (Fig. 4d) was performed and showed that, in patients with bone-only metastases, those who received chemotherapy had a significantly longer OS than those who did not before the landmark point of 35 months. However, significantly shorter OS after 35 months was otherwise observed in those patients receiving chemotherapy.
Table 3

Univariate and multivariate Cox regression for all-cause mortality based on treatment modalities and metastatic sites

Groups

Variables

Level

n

Univariate

Multivariate

HR (95% CI)

p value

HR (95% CI)

p value

Bone-only

(n = 14,872)

Surgery

No/unknown

13,475

1

 

1

 

Endoscopic therapy

1191

0.975 (0.898–1.058)

0.539

1.106 (1.016–1.204)

0.020

RP

206

0.187 (0.128–0.274)

< 0.001

0.339 (0.231–0.495)

< 0.001

RT

No/unknown

11,584

1

 

1

 

EBRT

3194

0.898 (0.850–0.949)

< 0.001

0.954 (0.902–1.009)

0.097

Brachytherapy

94

0.396 (0.272–0.578)

< 0.001

0.567 (0.388–0.829)

0.003

Chemo

No/unknown

13,015

1

 

1

 

Yes

1857

0.761 (0.700–0.827)

< 0.001

0.850 (0.781–0.924)

< 0.001

Bone and lung

(n = 976)

Surgery

No/unknown

899

1

   

Endoscopic therapy

72

0.844 (0.609–1.169)

0.308

  

RP

5

  

RT

No/unknown

758

1

   

EBRT

216

0.915 (0.744–1.125)

0.400

  

Brachytherapy

2

  

Chemo

No/unknown

808

1

 

1

 

Yes

168

0.643 (0.483–0.855)

0.002

0.737 (0.552–0.984)

0.039

Bone and liver

(n = 414)

Surgery

No/unknown

355

1

   

Endoscopic therapy

57

0.970 (0.707–1.332)

0.852

  

RP

2

  

RT

No/unknown

333

1

   

EBRT

80

0.898 (0.673–1.198)

0.464

  

Brachytherapy

1

  

Chemo

No/unknown

306

1

 

1

 

Yes

108

0.629 (0.477–0.830)

0.001

0.651 (0.491–0.864)

0.003

Bone and brain

(n = 126)

Surgery

No/unknown

122

1

   

Endoscopic therapy

2

  

RP

2

  

RT

No/unknown

78

1

   

EBRT

46

1.015 (0.668–1.541)

0.944

  

Brachytherapy

2

  

Chemo

No/unknown

107

1

   

Yes

19

0.577 (0.314–1.062)

0.077

  

Bone and ≥ 2 other sites

(n = 255)

Surgery

No/unknown

234

1

   

Endoscopic therapy

21

0.872 (0.474–1.606)

0.661

  

RT

No/unknown

184

1

   

EBRT

71

1.007 (0.730–1.390)

0.965

  

Chemo

No/unknown

191

1

   

Yes

64

1.009 (0.709–1.43600)

0.959

  

Multivariate analysis was adjusted for age, marriage, race, PSA, and Gleason score

Fig. 4

Kaplan-Meier survival curves and log-rank tests showing OS in prostate cancer patients with bone-only metastases. a OS differences between patients who underwent RP, endoscopic therapy and non/unknown surgery. b OS differences between patients who underwent brachytherapy, EBRT and non/unknown RT. c OS differences between patients who underwent chemotherapy and non/unknown chemotherapy. d Landmark analysis discriminating between patients who underwent chemotherapy and non/unknown chemotherapy

Discussion

Younger age and married status were associated with prolonged OS

Previous studies based on the SEER database have reported that the median age of localized and locally advanced PCa patients are 61 and 65 years, respectively [15, 16]. Our study found that PCa patients with bone metastases were significantly older than those with localized and locally advanced PCa patients, with a median age of 71 years. Meanwhile, older age (age > 70 years) was associated with a poor prognosis, consistent with previous reports [12, 17, 18].

Studies based on the SEER database have reported that the married proportion of localized and locally advanced PCa patients are 77% and 71%, respectively [15, 16]. In our study, the proportion of married PCa patients with bone metastases was lower than that of localized and locally advanced PCa patients (54% vs 77% and 71%). Conceivably, this is because PCa patients with bone metastases were older and more likely to be widowed than younger patients. Meanwhile, an unmarried status was also associated with a worse survival, possibly due to married patients more easily to receive social and financial support from their families and to choose a proactive treatment. As reported in previous studies, marital status is a prognostic factor for the better survival in PCa patients [19, 20].

In addition, our study indicated that high pathological grades, high PSA levels (> 50 ng/ml), and high Gleason scores (Gleason score ≥ 8) of the tumor were associated with a worse OS. These findings are in line with those of former studies [12, 17, 21].

Asian or Pacific Islander ethnic background was associated with favorable OS

Several studies have reported that for localized and locally advanced PCa patients, Black men consistently have a higher mortality rate than do men of other ethnicities. One possible reason for this finding is that Black men are less likely to be treated with a curative intent than are White men [22, 23]. However, in our study, Black men presented survival times similar to those of White men. This phenomenon might be explained by the fact that in the metastatic stage, there are few proactive treatments available to significantly change the oncological outcome of these patients. Interestingly, our study demonstrated that patients with an Asian or Pacific Islander background were associated with a better OS than White men, which is consistent with previous reports showing that Asian men have superior survival in de novo metastatic PCa than do men of other races [24]. Therefore, genomic diversities rather than treatments are most accountable for the different survival times between races [24]. It is known that allelic imbalance at 13q14 and 13q21 is significantly higher in Japanese patients than in Caucasians [25]. The frequency of the TMPRSS2-ERG fusion in Chinese patients is significantly lower than those patients from Western countries [26]. Furthermore, differences in diet (e.g., soy food consumption, which is popular in Asians and associated with a 25% to 30% reduced risk of PCa) and other lifestyle factors may also affect survival [24, 27].

Lung was the most frequent site of synchronous metastases

Our study shows that in PCa patients with bone metastases, approximately 10% of patients have synchronous distant metastases at other sites. Among these sites, the lung was the most frequently involved extra-skeletal organ, followed by the liver, whereas brain metastasis was relatively uncommon. These results are in line with those of former studies [18, 28]. A previous autopsy study of 1589 PCa patients also demonstrated that lung was the second most frequent site of involvement, following bone [29]. However, there is very few published researches on the mechanisms of lung metastasis in prostate cancer. Several biological processes, such as hemodynamics, bone-specific signaling interactions, and the “seed and soil” hypothesis, were attributable to the bone metastasis of PCa [30]. Lung metastasis of breast cancer, another primary of high incidence and metastatic rate, is often explained by the “seed and soil” hypothesis [31]. To elucidate the mechanism of lung metastasis from PCa remains a challenge, which need further study to understand its pathogenesis and prognosis.

Liver metastases were associated with poor OS

As described in the results section, we observed significant associations between the sites of metastases and patients’ survival. In particular, patients with liver metastases showed a poorer prognosis than those with other types of metastases. It is important to understand which of the two factors, the number of metastatic sites and the specific site of metastases, has a greater impact on the prognosis of patients. For this purpose, we analyzed PCa patients with lung-only, brain-only, and liver-only metastases using Kaplan–Meier survival curves and log-rank tests and found that patients with liver metastases showed the worst prognosis (Additional file 1: Fig. S1A). Kaplan–Meier survival curves and log-rank tests showed that as long as a patient had liver metastases, no matter how many other sites of metastases were present, the survival time was expected to be similarly short (Additional file 1: Fig. S1B). However, this phenomenon was not seen in patients with lung or brain metastases, as the number of metastatic sites significantly affected prognosis (Additional file 1: Fig. S1C and D).

It is known that PCa patients with liver metastases often have a lower Karnofsky Performance Status (KPS) scores [32]. Patients with low KPS scores cannot tolerate intensive systemic treatment. Another potential reason is that liver metastases from PCa tend to have a propensity for neuroendocrine differentiation, which is independently associated with poor survival outcomes [30, 33]. The neuroendocrine differentiation propensity in liver metastasis patients was also observed in our cohort. In PCa patients with bone-only metastases, neuroendocrine differentiation consisted of only 0.7%, whereas in bone and liver metastases, the rate rose up to 7% of the patients (Additional file 2: Table S1). These results suggest that we need to carefully evaluate the synchronous metastases of extra-skeletal organs prior to treatment in PCa patients with initial bone metastases.

Chemotherapy improved OS in specific patient subpopulations

With regard to treatment, our study revealed that surgery, RT, and chemotherapy were uncommonly used in de novo PCa patients with bone metastases, with rates of only 9.6%, 22.6%, and 13.3%, respectively. This phenomenon was related to the fact that ADT had been the first line of treatment for metastatic PCa patients for many years [34].The addition of chemotherapy to impact PCa survival was first examined in castration-resistant prostate cancer (CRPC) in 2004. Since then, additional studies have described the role of chemotherapy increasingly earlier in disease presentation [35]. In recent years, several studies have supported the upfront use of chemotherapy at the initial diagnosis of metastatic prostate cancer. For example, in a large phase III trial, CHAARTED, the addition of 6-cycle docetaxel chemotherapy to ADT in men with newly diagnosed hormone-naive PCa resulted in a 14-month improvement in median survival (57.6 vs. 44 M) [36]. And the phase III study of ADT alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15) found that, the addition of 9-cycle docetaxel chemotherapy to ADT in radiologically confirmed metastatic PCa resulted in modest OS benefits (60 vs. 54 M) [37]. Therefore, only in recent years has chemotherapy been recommended by the NCCN and EAU guidelines for certain metastatic PCa patients who are fit enough to receive the combination treatment at initial diagnosis [10, 11]. In our study, similarly, when all patients were pooled for multivariate Cox analysis, chemotherapy had a positive role in reducing the risk of mortality, with an HR of 0.848.

Interestingly, landmark analysis showed that, compared with bone-only metastases patients receiving no chemotherapy, patients receiving chemotherapy had a significantly longer OS before the landmark point of 35 months. However, significantly shorter OS after 35 months was otherwise observed. The reasons may include (1) the Kaplan–Meier analysis was not adjusted for age, marriage, race, PSA, Gleason score, etc., whereas the results of the multivariate Cox regression were adjusted for the above variable and showed that chemotherapy prolonged OS; and (2) as recommended by the NCCN and EAU guidelines, patients with a low-volume metastatic disease have less certain benefit from early-delivered chemotherapy. Therefore, we might assume that the majority of patients receiving chemotherapy tend to be of high-volume disease, which may affect patients’ long-term survival. In addition, it is noted that more than 93% of chemotherapy patients deceased before 35 months, while only less than 7% of chemotherapy patients stayed alive after 35-month. Therefore, the power of Kaplan–Meier analysis may be limited.

Another interesting result was that, although chemotherapy was an independent prognostic factor in patients with only bone, bone and lung, and bone and liver metastases, it was not in patients with bone and brain, or bone metastases and ≥ 2 other sites (including some brain metastases) of metastases. These results indicate that chemotherapy only improves OS in patients without brain metastases, which might be explained by the effect of the blood–brain barrier on the efficacy of chemotherapy [38]. Experimentally, van der Veldt et al. [39] once reported very low uptake of docetaxel in the brain of PCa patients receiving chemotherapy.

RP and BT improved OS in patients with bone-only metastases

In our study, when all patients were pooled for multivariate Cox analysis, neither surgery nor RT had an effect in reducing the risk of mortality, with HRs of 1.006 and 0.955, respectively. Therefore, all patients were stratified according to the sites of metastases and treatment modalities for further evaluation of survival benefits. Although, in our study, in the group of PCa patients with bone-only metastases, only 206 and 94 patients underwent RP and BT, respectively. Interestingly, RP and BT both presented significant benefits in reducing the risk of mortality, with HRs of 0.339 and 0.567, respectively. However, similar to PCa patients with bone-only metastases, RP and BT were rarely used in PCa patients with bone metastases and other sites of metastases. Due to the small amount of data, multivariate Cox analysis was not possible. In 2014, Culp et al. [12] reported that local therapy with RP and BT appeared to confer a survival benefit for metastatic PCa. Our study, therefore, provided meaningful support to the study by Culp et al., as we pointed out that the benefits of RP and BT were mainly observed in PCa patients with bone-only metastases. Due to the small sample size, further investigation is warranted to validate these findings.

EBRT to the primary tumor was strongly discouraged for metastatic PCa patients in the NCCN and EAU guidelines in the versions issued prior to 2019. EBRT was often used to palliate metastatic bone pain, spinal cord compression, and obstructive symptoms due to the primary tumor [40, 41]. However, in the most recent version of the NCCN and EAU guidelines, EBRT combined with ADT was recommended for metastatic PCa patients who had a low metastatic burden according to the CHAARTED criteria (a high metastatic burden was defined as four or more bone metastases with one or more metastases outside of the vertebral body or pelvis, or visceral metastases, or both; all other assessable patients were considered to have a low metastatic burden) [10, 11]. This updated recommendation was based on the STAMPEDE phase 3 randomized trial, which was reported in 2018 and suggested that prostate RT improves OS for men with metastatic PCa who have a low metastatic burden but not for all patients [42]. Since the SEER database does not provide information on the sites of RT, we assumed that BT was RT for the primary lesion, while EBRT may have been RT for the primary or metastatic lesion. This finding may explain why the BT group showed a longer OS, while the EBRT group showed no OS advantage in de novo PCa patients with bone-only metastases in our study.

Similar to other studies that have utilized the SEER database as their data source, our study did have certain limitations. First, only four distant sites of metastases were assessed, and details on the metastases, such as the sizes and exact metastatic lesion quantity in specific organs, were lacking. Second, all information on metastases was from the initial diagnosis, and there was a lack of follow-up information. Third, although the SEER data included information regarding the use of surgery, RT, and chemotherapy, the details of these therapies (i.e., surgical margins, radiation dose, radiation to the primary tumor, chemotherapy regimen and chemotherapy sequence) were not recorded in the database. Fourth, some other treatment information that might be important for prognosis, such as ADT and abiraterone acetate, was lacking.

Conclusions

In summary, our study found that age, race, tumor grade, PSA, Gleason score, sites of synchronous extra-skeletal metastases, as well as treatment modalities affected OS in newly diagnosed PCa patients with bone metastases. Specifically, (1) Asian or Pacific Islander ethnic background was associated with prolonged OS, which may be a combined result of genomic and lifestyle factors; (2) lung was the most frequent site of synchronous metastases; (3) liver metastases were associated with the worst prognosis; (4) chemotherapy improved OS in specific patient subpopulations without brain metastasis; and (5) RP and BT improved OS in patients with bone-only metastases, which need to be validated in further investigations due to limited cohort size of the current study.

Notes

Acknowledgements

We thank the SEER program of the National Cancer Institute (NCI) for providing these data. The authors gratefully thank the academic editor and the anonymous reviewers for their constructive suggestions to improve this manuscript.

Authors’ contributions

Conceptualization, FZ, XC and SY; data curation, JW, MC and DC; formal analysis, FZ, SY and XL; methodology, FZ and SY; supervision, GR and SY; visualization, JW and MC; Writing—original draft, FZ; writing—review and editing, FZ, GR and SY. All authors read and approved the final manuscript.

Funding

This study was supported by the National Nature Science Foundation of China (81701683) and Zhejiang Provincial Key Discipline of Traditional Chinese Medicine (2017-XK-A32).

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Supplementary material

40169_2019_247_MOESM1_ESM.jpg (1.4 mb)
Additional file 1: Figure S1. Kaplan-Meier survival curves and log-rank tests showing overall survival in PCa patients with only one site metastases, lung metastases, brain metastases, and liver metastases. A: Patients with liver metastases showed the worst prognosis. B: As long as a patient had liver metastases, no matter how many other sites of metastases were present, the survival time was expected to be similarly short. C: OS differences between patients with lung-only metastases (1 site), lung and another site metastases (2 sites), and lung and ≥ 2 other sites metastases (≥ 3 sites). D: OS differences between patients with brain-only metastases (1 site), brain and another site metastases (2 sites), and brain and ≥ 2 other sites metastases (≥ 3 sites).
40169_2019_247_MOESM2_ESM.docx (12 kb)
Additional file 2: Table S1. Pathology types (ICD-0-3) of PCa patients with bone-only metastases, bone and lung metastases, bone and liver metastases, bone and brain metastases, and bone and ≥ 2 other sites metastases.

References

  1. 1.
    Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH et al (2016) Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 66(4):271–289PubMedCrossRefGoogle Scholar
  2. 2.
    Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Sathiakumar N, Delzell E, Morrisey MA, Falkson C, Yong M, Chia V et al (2011) Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US Medicare beneficiaries, 1999–2006. Prostate Cancer Prostatic Dis 14(2):177–183PubMedCrossRefGoogle Scholar
  4. 4.
    Nørgaard M, Jensen AØ, Jacobsen JB, Cetin K, Fryzek JP, Sørensen HT (2010) Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol 184(1):162–167PubMedCrossRefGoogle Scholar
  5. 5.
    Zhuo L, Cheng Y, Pan Y, Zong J, Sun W, Xu L et al (2019) Prostate cancer with bone metastasis in Beijing: an observational study of prevalence, hospital visits and treatment costs using data from an administrative claims database. BMJ Open 9(6):e028214PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Patrikidou A, Loriot Y, Eymard JC, Albiges L, Massard C, Ileana E et al (2014) Who dies from prostate cancer? Prostate Cancer Prostatic Dis. 17(4):348–352PubMedCrossRefGoogle Scholar
  7. 7.
    Afriansyah A, Hamid ARA, Mochtar CA, Umbas R (2019) Survival analysis and development of a prognostic nomogram for bone-metastatic prostate cancer patients: a single-center experience in Indonesia. Int J Urol 26(1):83–89PubMedCrossRefGoogle Scholar
  8. 8.
    Guo Q, Zhang C, Guo X, Tao F, Xu Y, Feng G et al (2018) Incidence of bone metastasis and factors contributing to its development and prognosis in newly diagnosed renal cell carcinoma: a population-based study. Cancer Manag Res 28(10):2935–2944CrossRefGoogle Scholar
  9. 9.
    Leone BA, Vallejo CT, Romero AO, Machiavelli MR, Pérez JE, Leone J et al (2017) Prognostic impact of metastatic pattern in stage IV breast cancer at initial diagnosis. Breast Cancer Res Treat 161(3):537–548PubMedCrossRefGoogle Scholar
  10. 10.
    EAU Guidelines. Edn. presented at the EAU Annual Congress Barcelona 2019. ISBN 978-94-92671-04-2. EAU Guidelines Office, Arnhem, The Netherlands. http://uroweb.org/guidelines/compilations-of-all-guidelines/
  11. 11.
    National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, Prostate Cancer (Version 2.2019). https://www.nccn.org/professionals/physician_gls/. Accessed 17 Apr 2019
  12. 12.
    Culp SH, Schellhammer PF, Williams MB (2014) Might men diagnosed with metastatic prostate cancer benefit from definitive treatment of the primary tumor? A SEER-based study. Eur Urol 65(6):1058–1066PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Norum J, Nieder C (2017) Treatments for metastatic prostate cancer (mPC): a review of costing evidence. Pharmacoeconomics 35(12):1223–1236PubMedCrossRefGoogle Scholar
  14. 14.
    Cho Y, Chang JS, Rha KH, Hong SJ, Choi YD, Ham WS et al (2016) Does radiotherapy for the primary tumor benefit prostate cancer patients with distant metastasis at initial diagnosis? PLoS ONE 11(1):e0147191PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Bandini M, Marchioni M, Preisser F, Zaffuto E, Tian Z, Tilki D et al (2018) Survival after radical prostatectomy or radiotherapy for locally advanced (cT3) prostate cancer. World J Urol 36(9):1399–1407PubMedCrossRefGoogle Scholar
  16. 16.
    Preisser F, Mazzone E, Knipper S, Nazzani S, Bandini M, Shariat SF et al (2019) Rates of positive surgical margins and their effect on cancer-specific mortality at radical prostatectomy for patients with clinically localized prostate cancer. Clin Genitourin Cancer 17(1):e130–e139PubMedCrossRefGoogle Scholar
  17. 17.
    Yamamoto T, Musunuru HB, Vesprini D, Zhang L, Ghanem G, Loblaw A et al (2016) Metastatic prostate cancer in men initially treated with active surveillance. J Urol 195(5):1409–1414PubMedCrossRefGoogle Scholar
  18. 18.
    Guo Y, Mao S, Zhang A, Wang R, Zhang Z, Zhang J et al (2019) Prognostic significance of young age and non-bone metastasis at diagnosis in patients with metastatic prostate cancer: a SEER population-based data analysis. J Cancer 10(3):556–567PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Liu Y, Xia Q, Xia J, Zhu H, Jiang H, Chen X et al (2019) The impact of marriage on the overall survival of prostate cancer patients: a Surveillance, Epidemiology, and End Results (SEER) analysis. Can Urol Assoc J 13(5):E135–E139PubMedGoogle Scholar
  20. 20.
    Deng Y, Bi R, Zhu Z, Li S, Xu B, Rather WA et al (2019) A surveillance, epidemiology and end results database analysis of the prognostic value of organ-specific metastases in patients with advanced prostatic adenocarcinoma. Oncol Lett 8(2):1057–1070Google Scholar
  21. 21.
    Rusthoven CG, Carlson JA, Waxweiler TV, Yeh N, Raben D, Flaig TW et al (2014) The prognostic significance of Gleason scores in metastatic prostate cancer. Urol Oncol 32(5):707–713PubMedCrossRefGoogle Scholar
  22. 22.
    Mahal BA, Aizer AA, Ziehr DR, Hyatt AS, Sammon JD, Schmid M et al (2014) Trends in disparate treatment of African American men with localized prostate cancer across National Comprehensive Cancer Network risk groups. Urology 84(2):386–392PubMedCrossRefGoogle Scholar
  23. 23.
    Mahal BA, Aizer AA, Ziehr DR, Hyatt AS, Choueiri TK, Hu JC et al (2014) Racial disparities in prostate cancer-specific mortality in men with low-risk prostate cancer. Clin Genitourin Cancer 12(5):e189–e195PubMedCrossRefGoogle Scholar
  24. 24.
    Bernard B, Muralidhar V, Chen YH, Sridhar SS, Mitchell EP, Pettaway CA et al (2017) Impact of ethnicity on the outcome of men with metastatic, hormone-sensitive prostate cancer. Cancer 123(9):1536–1544PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Misumi T, Yamamoto Y, Murakami T, Kawai Y, Ito H, Eguchi S et al (2010) Genetic alterations at 13q14 may correlate with differences in the biological behavior of prostate cancer between Japanese and Caucasian men. Urol Int 84(4):461–466PubMedCrossRefGoogle Scholar
  26. 26.
    Ren S, Peng Z, Mao JH, Yu Y, Yin C, Gao X et al (2012) NA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings. Cell Res 22(5):806–821PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Kimura T (2012) East meets West: ethnic differences in prostate cancer epidemiology between East Asians and Caucasians. Chin J Cancer 31(9):421–429PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Shou J, Zhang Q, Wang S, Zhang D (2018) The prognosis of different distant metastases pattern in prostate cancer: a population based retrospective study. Prostate 78(7):491–497PubMedCrossRefGoogle Scholar
  29. 29.
    Bubendorf L, Schöpfer A, Wagner U, Sauter G, Moch H, Willi N et al (2000) Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 31(5):578–583PubMedCrossRefGoogle Scholar
  30. 30.
    Manna F, Karkampouna S, Zoni E, De Menna M, Hensel J, Thalmann GN et al (2019) Metastases in prostate cancer. Cold Spring Harb Perspect Med. 9(3):a033688PubMedCrossRefGoogle Scholar
  31. 31.
    Piaseczny MM, Allan AL (2014) Why does breast cancer often spread to the lung? Womens Health (Lond) 10(6):561–564CrossRefGoogle Scholar
  32. 32.
    Pond GR, Sonpavde G, de Wit R, Eisenberger MA, Tannock IF, Armstrong AJ (2014) The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer. Eur Urol 65(1):3–6PubMedCrossRefGoogle Scholar
  33. 33.
    Pouessel D, Gallet B, Bibeau F, Avancès C, Iborra F, Sénesse P et al (2007) Liver metastases in prostate carcinoma: clinical characteristics and outcome. BJU Int 99(4):807–811PubMedCrossRefGoogle Scholar
  34. 34.
    Bouchot O, Lenormand L, Karam G, Prunet D, Gaschignard N, Malinovsky JM et al (2000) Intermittent androgen suppression in the treatment of metastatic prostate cancer. Eur Urol 38(5):543–549PubMedCrossRefGoogle Scholar
  35. 35.
    Hurwitz MD (2018) Chemotherapy and radiation for prostate cancer. Transl Androl Urol 7(3):390–398PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M et al (2015) Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373(8):737–746PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Gravis G, Boher JM, Joly F, Soulié M, Albiges L, Priou F et al (2016) Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol 70(2):256–262PubMedCrossRefGoogle Scholar
  38. 38.
    Caffo O, Gernone A, Ortega C, Sava T, Cartenì G, Facchini G et al (2012) Central nervous system metastases from castration-resistant prostate cancer in the docetaxel era. J Neurooncol 107(1):191–196PubMedCrossRefGoogle Scholar
  39. 39.
    Van der Veldt AA, Hendrikse NH, Smit EF, Mooijer MP, Rijnders AY, Gerritsen WR et al (2010) Biodistribution and radiation dosimetry of 11C-labelled docetaxel in cancer patients. Eur J Nucl Med Mol Imaging 37(10):1950–1958PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Siva S, Bressel M, Murphy DG, Shaw M, Chander S, Violet J et al (2018) Stereotactic abative body radiotherapy (SABR) for oligometastatic prostate cancer: a prospective clinical trial. Eur Urol 74(4):455–462PubMedCrossRefGoogle Scholar
  41. 41.
    Osborn JL, Getzenberg RH, Trump DL (1995) Spinal cord compression in prostate cancer. J Neurooncol 23(2):135–147PubMedCrossRefGoogle Scholar
  42. 42.
    Parker CC, James ND, Brawley CD, Clarke NW, Hoyle AP, Ali A et al (2018) Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet 392(10162):2353–2366PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© The Author(s) 2019

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Authors and Affiliations

  1. 1.Department of Radiation OncologyThe First Affiliated Hospital, College of Medicine, Zhejiang UniversityHangzhouPeople’s Republic of China
  2. 2.Graduate School, College of MedicineZhejiang UniversityHangzhouPeople’s Republic of China
  3. 3.Department of UrologyThe First Affiliated Hospital, College of Medicine, Zhejiang UniversityHangzhouPeople’s Republic of China
  4. 4.Institute of Pharmaceutical Biotechnology and the First Affiliated Hospital, College of MedicineZhejiang UniversityHangzhouPeople’s Republic of China
  5. 5.Department of PathologyThe First Affiliated Hospital, College of Medicine, Zhejiang UniversityHangzhouPeople’s Republic of China

Personalised recommendations