Purpose: The purpose of this study is to investigate the clinical oncological outcomes and prognostic factors of high-volume disease (HVD) in the Asian population with metastatic hormone-sensitive prostate cancer. Methods: We retrospectively analyzed 503 patients with newly diagnosed metastatic prostate cancer. Patients were classified as HVD if visceral metastases were present and/or ≥4 bone lesions with ≥1 lesion beyond the vertebral bodies and pelvis. Overall survival (OS) and cancer-specific survival were investigated based on the disease burden. The Cox proportional hazards regression model was used to evaluate the prognostic factors. Results: About 50.7% patients were classified as low-volume disease (LVD) and 49.3% were HVD at diagnosis. The medians of OS and cancer-specific survival were 64 and 116 months, respectively, for patients with LVD and 26 and 46 months, respectively, for men with HVD (both P < 0.001). Among patients with HVD, 76.6% had both high-volume bone disease (HBD) (≥4 bone metastases) and appendicular bone involvement. There was no significant difference in both OS and cancer-specific survival between patients with visceral metastases and those with HBD combined with appendicular bone involvement. In the multivariable analysis, presence of Gleason score ≥8, HBD, or HVD may predict poorer OS and cancer-specific survival outcomes (all P < 0.05). Conclusions: Asian patients with high-volume metastatic prostate cancer had a larger proportion of HBD with appendicular bone involvement, who had a comparably poor prognosis to those with visceral metastases. Patients with HBD or HVD had reduced survival outcomes.
Keywords: Asian continental ancestry group, neoplasm metastasis, prognosis, prostatic neoplasms
|How to cite this URL:|
Cheng YT, Hong JH, Lu YC, Pu YS, Huang CY, Huang KH, Liu SP, Chen CH. Impact of high-Volume disease in Asian population with newly diagnosed metastatic prostate cancer. Urol Sci [Epub ahead of print] [cited 2019 Jan 19]. Available from: http://www.e-urol-sci.com/preprintarticle.asp?id=233159
| Introduction|| |
Western men have a 50-60 times higher rates of prostate cancer diagnosis than do Asian population., In the United States, it is estimated that 26,120 men die from prostate cancer in 2016, accounting for 8% of cancer deaths. Prostate cancer incidence increases rapidly with an annual increase rate of 5.6% in Taiwan and is currently the fifth common cancer in males.
Lymph nodes and bone are the most common metastatic sites for prostate cancer, whereas visceral involvement or multiple metastases represent a more aggressive disease. The disease burden has been used to be an important prognostic factor for group stratification in multiple clinical trials.,,,, However, the varied definitions of disease burden resulted in the difficulty of comparison among study series. Androgen deprivation therapy (ADT) acted as the mainstay treatment of metastatic prostate cancer. Progression to metastatic castration-resistant prostate cancer (mCRPC) occurred within a median duration of 11.7–16 months. Attempts to improve the survival duration by chemohormonal therapy in metastatic hormone-sensitive prostate cancer (mHSPC) patients were examined.,,
In chemohormonal androgen ablation randomized trial in prostate cancer (CHAARTED) trial, chemohormonal therapy provided an overall survival (OS) benefit especially in patients with high-volume disease (HVD). Among the study, HVD was defined as the presence of visceral metastases and/or ≥4 bone lesions with ≥1 lesion beyond the vertebral bodies and pelvis. Distinct proportions of HVD existed between ethnic groups. Although more poorly differentiated and metastatic prostate cancer patients are identified in Asian countries, Asian metastatic prostate cancer patients have better survival duration compared with other ethnic patients., However, there are lack of details about the disease burden in previous studies, leading to a possible bias. Whether the tumor volume should be regarded as a useful prognostic factor warrant further investigation. The case number of Asian men in the CHAARTED trial was too few to draw a statistical conclusion. Thus, we plan to evaluate the impact of disease extent on survival outcomes in Asian men with metastatic prostate cancer.
| Methods|| |
From June 1998 to April 2012, we retrospectively enrolled 551 patients, who were newly diagnosed as metastatic prostate adenocarcinoma. Metastases were determined by computed tomography and/or magnetic resonance imaging and/or bone scan. The number and site of metastases were confirmed by the radiologists. A total of 13 men were excluded because the metastasis was originated from the other cancers. Based on the definition of the CHAARTED trial, we classified our patients into the HVD if visceral metastases are present and/or ≥4 bone lesions with ≥1 lesion beyond the vertebral bodies and pelvis. Patients who did not fit these criteria were classified as the low-volume disease (LVD). During this stratification process, 35 men were excluded because of insufficient clinical records for the determination of disease volume status. A final of 503 patients were verified to be included in the analysis.
Age at diagnosis, initial clinical symptoms determined as the chief complain of patients in urology clinic, digital rectal examination findings, serum prostate-specific antigen (PSA) at diagnosis (normal value: PSA <4 ng/ml), clinical cancer staging, Gleason score, metastatic site, numbers of bone metastases, involvement of appendicular bone, follow-up duration, the use of ADT and chemotherapy, and progression to mCRPC were recorded. Bony lesions were confirmed by bone scan, computed tomography and/or magnetic resonance imaging. In this study, the volume of bone metastases was categorized according to the number of metastases, and those with ≥4 bone lesions were defined as high-volume bone disease (HBD). The criteria to determine the mCRPC status was based on the guidelines of the European Association of Urology in 2017 that castrate serum testosterone <50 ng/dL or 1.7 nmol/L plus either biochemical progression or radiological progression. Long-term survival status in this study was updated to December 2015 by Taiwan Cancer Registry.
The primary end-points are the OS and cancer-specific survival (CSS) between HVD and LVD. OS is defined as the duration from the time of diagnosis to the date of death by any cause. Cancer-specific survival refers to the duration from the time of diagnosis to the date of death from prostate cancer. The secondary end-points are castration-resistant-free survival in both HVD and LVD.
All statistical analyses were performed with SPSS version 20 (IBM Corp, Inc., Chicago, IL, USA). Nominal variables were presented as the mean and standard deviation, and nonnominal variables were presented as the median and interquartile range (IQR). The Chi-square test was used for categorical variables, and the Mann–Whitney U-test was used to compare the continuous variables. The Kaplan–Meier method was used to evaluate OS and CSS. Multivariable Cox proportional hazard regression model was used to identify significant prognostic factors of OS and CSS. All tests were two-sided with P < 0.05 considered statistically significant.
| Results|| |
In this 15-year retrospective cohort of 503 patients with newly diagnosed metastatic prostate cancer in National Taiwan University Hospital, the median age at diagnosis was 75 years old (IQR: 69–80 years old). The patients were stratified according to tumor burden, and LVD and HVD were defined in 255 (50.7%) and 248 (49.3%) patients, respectively [Table 1]. Patients with HVD had significantly more systemic symptoms as chief complain, higher serum PSA level at diagnosis, higher Gleason score, more visceral metastases, higher presence of HBD (≥4 bone lesions), more appendicular bone metastases, and higher alkaline phosphate level than those with LVD. Bone was the most common metastatic site found in both groups, detected in 96.5% (246/255) of patients with LVD, and 96.4% (239/248) of those with HVD. After stratifying the patients with HVD based on the definitions, 190 (76.6%) had HBD with appendicular bone involvement, 30 (12.1%) had visceral metastases, and 28 (11.3%) had visceral metastases and HBD with appendicular bone involvement. Among 30 patients in HVD with visceral metastases, 21 patients had concomitant <4 bone involvement, and nine patients had visceral alone metastases. Even among patients with LVD, 61 (25.6%) had HBD, and 135 (56.7%) had appendicular bone involvement. About 98.8% and 94.7% of patients received ADT in LVD and HVD, respectively, while the rest of the patients were too late to accept ADT when diagnosis because of the deteriorated clinical conditions and grave prognosis. The majority of patients accepted gonadotropin-releasing hormone agonist as the main treatment modality of ADT, while 18.5% (91/493) had accepted orchiectomy; 50.5% (249/493) had accepted combined androgen blockade. Eventually, 267 patients progressed to mCRPC status. About 35.6% (95/267) patients had been treated with chemotherapy, of whom 79/95 (83.2%) accepted docetaxel, and 11/95 (11.6%) accepted paclitaxel, cisplatin, and 5-fluorouracil plus leucovorin (TPHDFL). Only 7.5% (20/267) of patients accepted abiraterone acetate or enzalutamide after the drugs has been under use since 2012, six of whom were chemotherapy-naïve.
At the median follow-up of 70 months (range: From <1 month to 204 months; median follow-up duration for the survivors: 88 months), 348 men died of any cause, and 191 men died of prostate cancer, respectively. The major cause of nonprostate cancer death was contributed to infectious disease. The median duration of OS and CSS was 41 months (95% confidence interval [CI]: 34.3–47.7 months) and 88 months (95% CI: 71.5–104.5 months), respectively. Patients with LVD had longer median OS (64 vs. 26 months) and CSS (116 vs. 46 months) than those with HVD (both log-rank test P < 0.001), [Figure 1]a and [Figure 1]b. We further divided the patients who had HVD into HBD plus appendicular bone, visceral metastases, and all combined. There was no significant difference of OS and CSS among these three subgroups [Figure 2]. Among patients with visceral metastases in HVD, there was no difference in OS and CSS between visceral metastases alone and visceral ± other metastases [Figure 3] (P = 0.239 and 0.349, respectively). The median time to CRPC and time from CRPC to death was significantly shorter in patients with HVD than LVD [Figure 4], (18.0 vs. 40.5 months and 12.0 vs. 16.5 months, respectively; P < 0.001 and P = 0.031, respectively). However, there was no difference in CRPC-free survival rate between the subgroups of HVD (P = 0.08).
|Figure 1: Kaplan–Meier curves of (a) overall survival and (b) cancer-specific survival between patients with high-volume disease and low-volume disease. mo = Months; CI = Confidence interval|
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|Figure 2: Kaplan–Meier curves of (a) overall survival and (b) cancer-specific survival between subgroups of patients with the high-volume disease. mo = Months; CI = Confidence interval; HBD = High-bone disease|
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|Figure 3: Kaplan–Meier curves of (a) overall survival and (b) cancer-specific survival between visceral metastases and visceral ± other metastases in patients with high-volume disease. mo = Months; CI = Confidence interval|
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|Figure 4: Kaplan–Meier curves of (a) CRPC-free survival rate between patients with high-volume disease and low-volume disease and (b) CRPC-free survival rate between subgroups of patients with high-volume disease. CRPC = Castration-resistant prostate cancer; mo = Months; CI = Confidence interval; HBD = High-volume bone disease|
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Several prognostic factors were considered to predict poorer OS and CSS in the univariable analysis, including: patients who had systemic symptoms as initial presentation, higher PSA value >300 ng/dl, Gleason score 8–10, presence of visceral metastases, more than two metastatic sites, HVD, HBD, and involvement of appendicular bone [Table 2] and [Table 3]. All parameters were analyzed with multivariable Cox regression model. To avoid the confounding effect between HVD and HBD, separate analyses were made as models 1 and 2. Gleason score 8–10 was significantly associated with reduced OS and CSS. In particular, patients with HBD had 2.04-fold higher overall mortality (95% CI: 1.52–2.73, P < 0.001) and 2.28-fold higher cancer-specific mortality (95% CI: 1.55-3.36, P < 0.001) [model 1 in [Table 2] and [Table 3]. Similarly, patients with HVD had 2.31-fold higher overall mortality (95% CI: 1.76–3.04, P < 0.001) and 2.40-fold higher cancer-specific mortality (95% CI: 1.66–3.45, P < 0.001) [model 2 in [Table 2] and [Table 3].
|Table 2: Univariable and multivariable Cox regression analysis predicting overall mortality in patients diagnosed with metastatic prostate cancer|
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|Table 3: Univariable and multivariable Cox regression analysis predicting cancer-specific mortality in patients diagnosed with metastatic prostate cancer|
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Models 3 and 4 showed the result of multivariable analyses on stratification according to disease volume. Initial symptoms and Gleason score were more significant prognostic factors of overall mortality and cancer-specific mortality in patients with LVD than in those with HVD [model 3 and 4, in [Table 2] and [Table 3].
| Discussion|| |
Our cohort demonstrated the population before the widespread use of chemohormonal therapy, abiraterone and enzalutamide, which showed a natural course of de novo metastatic prostate cancer in the Asian population ranging from 1998 to 2012. The PSA test was introduced into Taiwan in 1987 and popularized in most facilities for health check-up between 1993 and 1996. Similar to Chinese and Singaporean population, a lower rate (4.3%) of abnormal PSA ≥4.0 ng/ml was noted in Taiwanese health examination program., Nevertheless, HVD accounted for 49.3% of metastatic prostate cancer in Taiwan, leading Taiwanese cohort an ideal model for observing the oncological outcomes between groups stratified by tumor burden. Among our patients with HVD, HBD with appendicular bone involvement was the major component and played a significant role in reducing survival outcome compared with visceral metastases.
Varied definitions of HVD or extensive disease were used to stratify patients who were tested for the treatment effect in several clinical trials.,, However, the differences of the definitions make comparing survival outcomes among study series with great difficulties. As the publication of the CHAARTED trial for treating metastatic prostate cancer, the definition of HVD gradually conversed to these features such as the number of metastases, appendicular bone metastases, and visceral involvement. This condition offered a uniform platform to compare outcomes throughout different studies and ethnics. Bernard et al. showed that HVD was more frequently noted in Hispanic men, Asian men, and American Indian men than non-Hispanic white men (P = 0.004). Non-Hispanic white patients and black patients did have comparable oncological outcomes for chemohormonal therapy after stratification of tumor volume. However, the case number of Asian men in the CHAARTED trial was too few (n = 8) to draw statistical conclusions.
Comparing with the ADT group in the CHAARTED trial, our cohort had a lesser proportion of patients with Gleason score 8–10 (54% vs. 70%), visceral metastases (12% vs. 17%), or HVD (49% vs. 64%). We selected a comparable subgroup based on the inclusion and exclusion criteria used in the CHAARTED trial during the same study period from 2006 to 2012. The subgroup of our patients with HVD (n = 104) had a worse OS duration of 27 months than those Western men in the CHAARTED trial (OS duration: 32 months) [Supplementary Figure 1]. Although there was potential selection bias, including performance status, compliance, etc., the difference between these two cohorts was most likely due to the old age of our patients.
Glass et al. demonstrated a prognostic model for mHSPC patients according to following risk factors: performance status, localization of bone disease (appendicular or axial skeleton), PSA value, and Gleason score. Gravis et al. published another simplified prognostic model based on GETUG-15 study and Glass risk model, which showed that Gleason score and visceral metastasis had no significant association with survival duration. However, the result was established from the cohort with smaller proportion of the extensive diseases.
In our series, Gleason score, HBD, and HVD were prognostic factors of both overall OS and CSS. After dividing the patients into low versus HVDs, initial symptoms and Gleason score showed significant prognostic values for OS and CSS in the patients with LVD. In multivariable analysis, PSA value at diagnosis was not a significant prognostic factor, likely because of its remarkable interaction with Gleason score. It might also imply the further stratification for such high PSA value is not necessary.
Some studies confirmed that the count of metastatic lesions had a great impact on clinical outcomes. During these decades, the concept of oligometastatic prostate cancer defined as five or less extrapelvic lesions emerges as an early status of widespread metastasis. Singh et al. also showed that the patients with ≤5 lesions of metastases had significantly better survival outcome than those with >5 lesions (P = 0.02). Similarly, several studies revealed that the extent of bony metastatic lesions is a prognostic indicator of the disease outcome., Soloway et al. described that patients with bone metastases of lesser than six lesions have significantly better survival than those with more. Tait et al. demonstrated that men with ≥5 bone metastases had worse progression-free survival and OS comparing with patients who had 1–4 metastases bone metastases. In this study, the patients with HBD (≥4 bone lesions) not only accounted for the majority presentation of HVD but also had poor survival outcomes in Asian patients.
In addition to the metastatic number, the metastatic site was also considered as an important contributor to prognosis. Pezaro et al. concluded that visceral metastases alone without extensive bone metastases may not represent an aggressive phenotype. According to Gandaglia et al., visceral metastases with concomitant bone involvement or multiple metastatic sites resulted in the worst outcome among metastatic prostate cancer patients. Pond et al. also showed that liver metastases followed by lung metastases were associated with shorter OS in men with mCRPC. In this study, survival rates had no significant difference between subgroups among patients with HVD [Figure 2] (P = 0.6 in OS and P = 0.9 in CSS). Whether patients with HVD had visceral metastasis alone or combined with other metastases did not affect the oncological outcome [Figure 3] (P = 0.2 in OS and P = 0.3 in CSS). Therefore, further research on the evolutionary process of cancer and biological heterogeneity was needed to explain the survival differences between metastatic location and extent.
With more treatment alternatives for mHSPC were confirmed, risk group stratification will be needed for the application of individualized cancer treatment. In addition to the great impact of the CHAARTED trial, LATITUDE trial published on June 2017 showed the survival benefit of ADT plus abiraterone acetate and prednisone in patients with mHSPC. The patients in LATITUDE trial were included based on at least two of the following high-risk factors: Gleason score ≥8, at least three bone lesions and visceral metastasis. Instead of highly selected patients from clinical trial or castration-resistant subgroup, the strength of this study was the result from a cohort of long-term follow-up in de novo noncastrate metastatic prostate cancer patients. We offer the prognostic information based on an Asian cohort, which might help physicians to better understand the natural course of the disease and make optimal therapeutic decisions in the future. The major limitation of this study was the nature of the retrospective design. Certain potential confounders and laboratory data which might affect the oncological outcomes were not assessable for the present study. Second, with the improvements of imaging facilities, the disease extent of metastatic prostate cancer could be diagnosed more precisely to redefine HVD in the future.
| Conclusions|| |
HVD accounted for half of the population in this Taiwanese cohort with metastatic prostate cancer. HBD with appendicular involvement had compatible poor prognosis with visceral metastases. Patients with Gleason score ≥8, HBD, or HVD had a reduced duration of OS and CSS.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Urology, National Taiwan University Hospital and College of Medicine, No. 7, Zhongshan South Road, Zhongzheng District, Taipei 100
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3]