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Asia-Pacific Journal of Clinical Oncology 2014
doi: 10.1111/ajco.12313
ORIGINAL ARTICLE
Survival outcomes of Chinese metastatic prostate cancer patients following primary androgen deprivation therapy in relation to prostate-specific antigen nadir level Jeremy Yuen Chun TEOH,1 James Hok Leung TSU,2 Steffi Kar Kei YUEN,2 Samson Yun Sang CHAN,1 Peter Ka Fung CHIU,1 Ka-Wing WONG,2 Kwan-Lun HO,2 Simon See Ming HOU,1 Chi-Fai NG1 and Ming Kwong YIU2 1 2
Division of Urology, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, and Division of Urology, Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
Abstract Aim: To evaluate the progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) of Chinese metastatic prostate cancer patients following primary androgen deprivation therapy (ADT) in relation to prostate-specific antigen (PSA) nadir level. Methods: All Chinese prostate cancer patients with bone metastases who were treated with primary ADT from 2000 to 2009 were included. Patients’ and disease characteristics were recorded. Patients were categorized into two PSA nadir groups (≤1.0 and >1.0 ng/mL). Associations of PSA nadir with PFS, CSS and OS were analyzed with Kaplan–Meier and Cox regression analyses. The survival outcomes of the two PSA nadir groups were presented. Results: Four hundred nineteen patients were included in the study. PSA nadir appeared to be a good predictor for PFS (hazard ratio [HR] 1.86, 95% confidence interval [CI] 1.35–2.56, P < 0.001), CSS (HR 1.60, 95% CI 0.98–2.64, P = 0.063) and OS (HR 1.77, 95% CI 1.20–2.41, P < 0.001) upon multivariate Cox regression analyses. In the PSA nadir groups of ≤1.0 and >1.0 ng/mL, the median PFS were 15 and 10 months, and the 1-year PFS rates were 64% and 40%, respectively; the median CSS were 42 and 27 months, and the 5-year OS rates were 53% and 28%, respectively; and the median OS were 41 and 24 months, and the 5-year OS rates were 45% and 19%, respectively. Conclusions: Higher PSA nadir was associated with shorter PFS, CSS and OS in Chinese metastatic prostate cancer patients following primary ADT. The survival outcomes may serve as references in deciding the best treatment strategy in Chinese prostate cancer patients. Key words: Chinese, metastasis, prostate cancer, prostate-specific antigen, survival.
INTRODUCTION Prostate cancer is a very common disease with an incidence of 214 cases per 1000 men in Europe.1 According to a Swedish population-based cohort study,2 prostate Correspondence: Dr Ming Kwong Yiu FRCSEd (Urol), FHKAM (Surgery), Division of Urology, Department of Surgery, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong, China. Email: [email protected] Conflict of interest: none Accepted for publication 6 October 2014.
© 2014 Wiley Publishing Asia Pty Ltd
cancer is the second most common cause of cancer death in men. Since the first report about the effects of surgical castration and estrogen administration on serum phosphatases by Huggins and Hodges in 1941,3 there has been increasing interests in the use of androgen deprivation therapy (ADT) in advanced prostate cancer. It has been shown that ADT can reduce bone pain and the incidence of pathological fracture and spinal cord compression.4 The use of ADT in men with prostate cancer has increased steadily throughout the 1990s,5 and it has become the mainstay of treatment in metastatic prostate cancer.
2
However, despite the initial good response to ADT, most patients will develop castration-resistant prostate cancer. It is important to identify those patients with prostate cancer of more aggressive behavior, and they may benefit from earlier consideration of other systemic treatment options. Prostate-specific antigen (PSA) nadir has been shown to be a good prognostic indicator in prostate cancer patients receiving ADT for biochemical recurrence after radical prostatectomy or radiotherapy.6–8 However, studies on the relationship between PSA nadir and survival outcomes in metastatic prostate cancer after ADT in the Chinese population are limited. Also, most of the studies included heterogeneous groups of patients with different clinical stages receiving various forms of primary treatment. We conducted this study to look into the role of PSA nadir in metastatic prostate cancer receiving primary ADT. We focused on newly diagnosed prostate cancer patients with bone metastases and aimed to provide survival data in this homogeneous group of patients based on their PSA nadir levels.
METHODS This is a retrospective review of all Chinese patients with metastatic prostate cancer who were treated with primary ADT (either in the form of bilateral orchiectomy or luteinizing hormone-releasing hormone agonists) in two university hospitals from year 2000 to 2009. Only patients with radiological or histological evidence of bone metastases were included. Patients who were given maximal androgen blockade were included, whereas patients who had prior radical prostatectomy or radical radiotherapy were excluded from our study. Patients’ and disease characteristics including age, Gleason score, clinical T-stage, baseline PSA and PSA nadir level were recorded. Survival outcomes including progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) were reviewed. Baseline PSA was defined as the PSA level before the initiation of ADT. PSA nadir was defined as the lowest PSA level achieved after the initiation of ADT. Progression was defined as at least two serial rises in PSA (taken at least one week apart) from its nadir level. Initiation of any secondary hormone treatment for rising PSA was also considered as a progression event. PSA nadir level was categorized into two groups: ≤1.0 and >1.0 ng/mL. The associations of PSA nadir with PFS, CSS and OS in the two PSA nadir groups were analyzed with Kaplan–Meier method, and the significance was determined by log-rank test. The
© 2014 Wiley Publishing Asia Pty Ltd
JYC Teoh et al.
prognostic significance of PSA nadir was further analyzed with univariate and multivariate Cox regression analyses. The median PFS, CSS and OS, and the 1-year to 5-year survival rates of the two PSA nadir groups were presented. A P-value of 1.0 ng/mL group. Upon univariate Cox regression analyses (Table 2), a higher Gleason score was associated with worse PFS (Gleason score 8–10, hazard ratio [HR] 1.79, 95% confidence interval [CI] 1.13–2.86, P = 0.014) and CSS (Gleason score 7, HR 2.25, 95% CI 1.05–4.84, P = 0.038; Gleason score 8–10, HR 2.30, 95% CI
Table 1
Patients’ and disease characteristics of the cohort
Mean age (years) Mean follow-up (months) Gleason score ≤6 7 8–10 Clinical T-stage 1 2 3/4 Median baseline PSA (ng/mL) PSA nadir groups (ng/mL) ≤1.0 >1.0 Median PSA nadir (ng/mL)
Value
Percentage
74.2 ± 8.3 44.8 ± 33.7
– –
– – –
10.6 22.2 67.2
– – – 212.3
8.1 48.3 42.6 –
– – 2.0
34.1 65.9 –
PSA, prostate-specific antigen.
Asia-Pac J Clin Oncol 2014
3
Survival in relation to PSA nadir
1.14–4.67, P = 0.021). A higher PSA nadir was associated with shorter PFS (HR 1.90, 95% CI 1.46– 2.47, P < 0.001), CSS (HR 1.73, 95% CI 1.16–2.56, P = 0.007) and OS (HR 1.97, 95% CI 1.53–2.53, P < 0.001). Upon multivariate analyses (Table 3), a higher PSA nadir was associated with shorter PFS (HR 1.86, 95% CI 1.35–2.56, P < 0.001) and OS (HR 1.77, 95% CI 1.20–2.41, P < 0.001). A higher PSA nadir also appeared to be associated with shorter CSS (HR 1.60, 95% CI 0.98–2.64, P = 0.063). Upon the end of the follow-up period, 74% of the patients developed disease progression after initial ADT. The median PFS were 15 and 10 months in the PSA nadir groups of ≤1.0 and >1.0 ng/mL, respectively. In the ≤1.0 ng/mL group, the PFS rates dropped gradually from 64% at 1 year to 10% at 5 years. The 1-year PFS rate in the >1.0 ng/mL group was 40%, which then dropped to 5% at 3 years and finally reached 2% at 5 years (Table 4). Concerning the CSS (Table 4), the median survival rates were 42 and 27 months in the PSA nadir groups of ≤1.0 and >1.0 ng/mL, respectively. The 1-year CSS rates (87% and 85%) in the PSA nadir groups of ≤1.0 and >1.0 ng/mL were similar. The CSS rates of the >1.0 ng/mL group then dropped relatively quicker than the ≤1.0 ng/mL group. The 5-year CSS rates were 53% and 28% in the PSA nadir groups of ≤1.0 and >1.0 ng/ mL, respectively. Concerning the OS (Table 4), the median survival were 41 and 24 months in the PSA nadir groups of ≤1.0 and >1.0 ng/mL, respectively. The OS rate in the ≤1.0 ng/mL group was 84% at 1 year, which then dropped gradually down to 45% at 5 years; the OS rate in the >1.0 ng/mL group was 77% at 1 year, which then dropped relatively quicker down to 19% at 5 years.
DISCUSSION
Figure 1 Kaplan–Meier analyses on the survival outcomes between the two prostate-specific antigen nadir groups. ADT, androgen deprivation therapy. ( ) 1.0; ( ) 1.0 – censored.
Asia-Pac J Clin Oncol 2014
ADT has been widely accepted in treating advanced prostate cancer. It has shown that ADT can reduce the incidence of pathological fracture, spinal cord compression, bilateral ureteral obstruction and extra-skeletal metastases.4 It is important to investigate for predictive factors of survival in order to identify those patients with high-risk disease. This is especially important for those with good general condition as other forms of systemic therapy can be considered early on. As evidence on the role of PSA nadir in Chinese prostate cancer patients with bone metastases following primary ADT is limited, we conducted this study to investigate the prog-
© 2014 Wiley Publishing Asia Pty Ltd
4
Table 2
JYC Teoh et al.
Univariate Cox regression analyses of clinicopathological factors predicting survival outcomes Progression-free survival
Age Gleason score ≤6 7 8–10 Clinical T-stage 1 2 3/4 Baseline PSA PSA nadir (ng/mL) ≤1.0 >1.0
Cancer-specific survival
Overall survival
HR (95% CI)
P-value
HR (95% CI)
P-value
HR (95% CI)
P-value
1.00 (0.98–1.01)
0.846
1.00 (0.98–1.02)
0.864
1.01 (0.99–1.03)
0.202
1.00 (Ref) 1.34 (0.80–2.26) 1.79 (1.13–2.86)
– 0.265 0.014
1.00 (Ref) 2.25 (1.05–4.84) 2.30 (1.14–4.67)
– 0.038 0.021
1.00 (Ref) 1.04 (0.66–1.63) 1.37 (0.92–2.05)
– 0.875 0.124
1.00 (Ref) 1.31 (0.84–2.03) 1.28 (0.82–1.99) 1.00 (1.00–1.00)
– 0.230 0.277 0.224
1.00 (Ref) 0.95 (0.51–1.78) 0.98 (0.52–1.84) 1.00 (1.00–1.00)
– 0.875 0.953 0.031
1.00 (Ref) 0.92 (0.60–1.41) 0.95 (0.62–1.46) 1.00 (1.00–1.00)
– 0.703 0.806 0.036
1.00 (Ref) 1.90 (1.46–2.47)
– 0.2 ng/mL was associated with shorter OS (HR 3.73, 95% CI 1.54–9.03, P = 0.003). In contrast to those patients with localized disease receiving curative treatment, either in the form of radical prostatectomy or radiotherapy, it is more difficult for metastatic prostate cancer patients receiving primary ADT to achieve an undetectable PSA nadir level. We decided to use 1.0 ng/mL as the cut-off level to categorize our patients into two groups for further analyses in our study. In our locality, bone scan is the usual standard workup for metastatic disease, and other imaging modalities including computed tomography scan, magnetic resonance imaging and positron emission tomography scan were not routinely performed. As this might affect the accuracy of the rates of lymph node or other distant metastases in our cohort, we decided to include only patients with bone metastases in our study. This would potentially yield more accurate results on this relatively homogeneous group of patients. In our study, a higher PSA nadir level was associated with shorter PFS, CSS and OS upon Kaplan–Meier analyses. A higher PSA nadir level was associated with shorter PFS (P < 0.001), CSS (P = 0.007) and OS (P < 0.001) upon univariate Cox regression analyses. Upon multivariate Cox regression analyses, although the association became insignificant for CSS (P = 0.063), the associations remained statistically significant for both PFS (P < 0.001) and OS (P < 0.001). We believe that PSA nadir is a promising prognostic indicator in metastatic prostate cancer patients receiving primary ADT. Up to 74% of our cohort had PSA progression after primary ADT and this is similar to that quoted in the literature.20 To our knowledge, this is the largest series investigating the prognostic significance of PSA nadir in Chinese prostate cancer patients with bone metastases following primary ADT. Due to the limited literature available in the Chinese population, our study aimed to provide Chinese-specific results that would be more applicable in managing prostate cancer in our locality. The strength of our study is the homogeneity of the patients included. The prognostic significance of PSA nadir shown by our
© 2014 Wiley Publishing Asia Pty Ltd
6
study is important in deciding the best treatment strategy in patients with disease progression after primary ADT; the survival data presented may translate into clinical use and are useful in counseling this group of patients. The main limitation is the retrospective nature of our study. Without a standard treatment and follow-up protocol, the data collected may not accurately reflect the situation. Serum testosterone level was not tested routinely in our patients, in which an adequate castration level could not be ascertained. The lack of information on the use of chemotherapy is another potential confounding factor that may affect our results. Apart from PFS, CSS and OS, clinical progression-free survival is another important aspect to look into. Unfortunately, due to the retrospective nature of our study, we do not have accurate information on the clinical progression in our cohort, and further studies are necessary to look into this. Moreover, other PSA kinetic parameters such as time to PSA nadir and PSA doubling time from nadir should be investigated. These parameters may possibly help identify patients with high-risk disease and provide useful information in deciding the best treatment strategy. Nevertheless, a comprehensive evaluation on the role of PSA nadir as a survival predictor for any additional treatment would require a high quality study in the form of randomized controlled trial. Further prospective trials with larger cohort size will be necessary in the future, especially in the context of Chinese population.
CONCLUSIONS In prostate cancer patients with bone metastases receiving primary ADT, a higher PSA nadir level is associated with shorter PFS, CSS and OS. The survival data may serve as a reference in deciding the best treatment strategy in patients with disease progression after primary ADT.
REFERENCES 1 Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC. Family history and the risk of prostate cancer. Prostate 1990; 17 (4): 337–47. 2 Gronberg H, Damber L, Damber JE. Familial prostate cancer in Sweden. A nationwide register cohort study. Cancer 1996; 77 (1): 138–43. 3 Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol 2002; 168 (1): 9–12.
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4 Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005; 294 (2): 238– 44. 5 Shahinian VB, Kuo YF, Freeman JL, Orihuela E, Goodwin JS. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005; 103 (8): 1615–24. 6 Keizman D, Huang P, Antonarakis ES et al. The change of PSA doubling time and its association with disease progression in patients with biochemically relapsed prostate cancer treated with intermittent androgen deprivation. Prostate 2011; 71 (15): 1608–15. 7 Stewart AJ, Scher HI, Chen MH et al. Prostate-specific antigen nadir and cancer-specific mortality following hormonal therapy for prostate-specific antigen failure. J Clin Oncol 2005; 23 (27): 6556–60. 8 Rodrigues NA, Chen MH, Catalona WJ, Roehl KA, Richie JP, D’Amico AV. Predictors of mortality after androgendeprivation therapy in patients with rapidly rising prostatespecific antigen levels after local therapy for prostate cancer. Cancer 2006; 107 (3): 514–20. 9 Benaim EA, Pace CM, Lam PM, Roehrborn CG. Nadir prostate-specific antigen as a predictor of progression to androgen-independent prostate cancer. Urology 2002; 59 (1): 73–8. 10 Choueiri TK, Xie W, D’Amico AV et al. Time to prostatespecific antigen nadir independently predicts overall survival in patients who have metastatic hormone-sensitive prostate cancer treated with androgen-deprivation therapy. Cancer 2009; 115 (5): 981–7. 11 Huang SP, Bao BY, Wu MT et al. Impact of prostatespecific antigen (PSA) nadir and time to PSA nadir on disease progression in prostate cancer treated with androgen-deprivation therapy. Prostate 2011; 71 (11): 1189–97. 12 Huang SP, Bao BY, Wu MT et al. Significant associations of prostate-specific antigen nadir and time to prostatespecific antigen nadir with survival in prostate cancer patients treated with androgen-deprivation therapy. Aging Male 2012; 15 (1): 34–41. 13 Soga N, Arima K, Sugimura Y. Undetectable level of prostate specific antigen (PSA) nadir predicts PSA biochemical failure in local prostate cancer with delayed-combined androgen blockade. Jpn J Clin Oncol 2008; 38 (9): 617– 22. 14 Hori S, Jabbar T, Kachroo N, Vasconcelos JC, Robson CN, Gnanapragasam VJ. Outcomes and predictive factors for biochemical relapse following primary androgen deprivation therapy in men with bone scan negative prostate cancer. J Cancer Res Clin Oncol 2011; 137 (2): 235– 41. 15 Morote J, Trilla E, Esquena S, Abascal JM, Reventos J. Nadir prostate-specific antigen best predicts the progression to androgen-independent prostate cancer. Int J Cancer 2004; 108 (6): 877–81.
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16 Kwak C, Jeong SJ, Park MS, Lee E, Lee SE. Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. J Urol 2002; 168 (3): 995–1000. 17 Kitagawa Y, Ueno S, Izumi K et al. Nadir prostate-specific antigen (PSA) level and time to PSA nadir following primary androgen deprivation therapy as independent prognostic factors in a Japanese large-scale prospective cohort study (J-CaP). J Cancer Res Clin Oncol 2014; 140 (4): 673–9. 18 Park YH, Hwang IS, Jeong CW, Kim HH, Lee SE, Kwak C. Prostate specific antigen half-time and prostate specific antigen doubling time as predictors of response to andro-
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gen deprivation therapy for metastatic prostate cancer. J Urol 2009; 181 (6): 2520–4, discussion 2525. 19 Miyamoto S, Ito K, Miyakubo M et al. Impact of pretreatment factors, biopsy Gleason grade volume indices and post-treatment nadir PSA on overall survival in patients with metastatic prostate cancer treated with step-up hormonal therapy. Prostate Cancer Prostatic Dis 2012; 15 (1): 75–86. 20 Sasaki T, Onishi T, Hoshina A. Nadir PSA level and time to PSA nadir following primary androgen deprivation therapy are the early survival predictors for prostate cancer patients with bone metastasis. Prostate Cancer Prostatic Dis 2011; 14 (3): 248–52.
© 2014 Wiley Publishing Asia Pty Ltd
Asia-Pacific Journal of Clinical Oncology 2014
doi: 10.1111/ajco.12313
ORIGINAL ARTICLE
Survival outcomes of Chinese metastatic prostate cancer patients following primary androgen deprivation therapy in relation to prostate-specific antigen nadir level Jeremy Yuen Chun TEOH,1 James Hok Leung TSU,2 Steffi Kar Kei YUEN,2 Samson Yun Sang CHAN,1 Peter Ka Fung CHIU,1 Ka-Wing WONG,2 Kwan-Lun HO,2 Simon See Ming HOU,1 Chi-Fai NG1 and Ming Kwong YIU2 1 2
Division of Urology, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, and Division of Urology, Department of Surgery, Queen Mary Hospital, University of Hong Kong, Hong Kong, China
Abstract Aim: To evaluate the progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) of Chinese metastatic prostate cancer patients following primary androgen deprivation therapy (ADT) in relation to prostate-specific antigen (PSA) nadir level. Methods: All Chinese prostate cancer patients with bone metastases who were treated with primary ADT from 2000 to 2009 were included. Patients’ and disease characteristics were recorded. Patients were categorized into two PSA nadir groups (≤1.0 and >1.0 ng/mL). Associations of PSA nadir with PFS, CSS and OS were analyzed with Kaplan–Meier and Cox regression analyses. The survival outcomes of the two PSA nadir groups were presented. Results: Four hundred nineteen patients were included in the study. PSA nadir appeared to be a good predictor for PFS (hazard ratio [HR] 1.86, 95% confidence interval [CI] 1.35–2.56, P < 0.001), CSS (HR 1.60, 95% CI 0.98–2.64, P = 0.063) and OS (HR 1.77, 95% CI 1.20–2.41, P < 0.001) upon multivariate Cox regression analyses. In the PSA nadir groups of ≤1.0 and >1.0 ng/mL, the median PFS were 15 and 10 months, and the 1-year PFS rates were 64% and 40%, respectively; the median CSS were 42 and 27 months, and the 5-year OS rates were 53% and 28%, respectively; and the median OS were 41 and 24 months, and the 5-year OS rates were 45% and 19%, respectively. Conclusions: Higher PSA nadir was associated with shorter PFS, CSS and OS in Chinese metastatic prostate cancer patients following primary ADT. The survival outcomes may serve as references in deciding the best treatment strategy in Chinese prostate cancer patients. Key words: Chinese, metastasis, prostate cancer, prostate-specific antigen, survival.
INTRODUCTION Prostate cancer is a very common disease with an incidence of 214 cases per 1000 men in Europe.1 According to a Swedish population-based cohort study,2 prostate Correspondence: Dr Ming Kwong Yiu FRCSEd (Urol), FHKAM (Surgery), Division of Urology, Department of Surgery, Queen Mary Hospital, University of Hong Kong, Pokfulam, Hong Kong, China. Email: [email protected] Conflict of interest: none Accepted for publication 6 October 2014.
© 2014 Wiley Publishing Asia Pty Ltd
cancer is the second most common cause of cancer death in men. Since the first report about the effects of surgical castration and estrogen administration on serum phosphatases by Huggins and Hodges in 1941,3 there has been increasing interests in the use of androgen deprivation therapy (ADT) in advanced prostate cancer. It has been shown that ADT can reduce bone pain and the incidence of pathological fracture and spinal cord compression.4 The use of ADT in men with prostate cancer has increased steadily throughout the 1990s,5 and it has become the mainstay of treatment in metastatic prostate cancer.
2
However, despite the initial good response to ADT, most patients will develop castration-resistant prostate cancer. It is important to identify those patients with prostate cancer of more aggressive behavior, and they may benefit from earlier consideration of other systemic treatment options. Prostate-specific antigen (PSA) nadir has been shown to be a good prognostic indicator in prostate cancer patients receiving ADT for biochemical recurrence after radical prostatectomy or radiotherapy.6–8 However, studies on the relationship between PSA nadir and survival outcomes in metastatic prostate cancer after ADT in the Chinese population are limited. Also, most of the studies included heterogeneous groups of patients with different clinical stages receiving various forms of primary treatment. We conducted this study to look into the role of PSA nadir in metastatic prostate cancer receiving primary ADT. We focused on newly diagnosed prostate cancer patients with bone metastases and aimed to provide survival data in this homogeneous group of patients based on their PSA nadir levels.
METHODS This is a retrospective review of all Chinese patients with metastatic prostate cancer who were treated with primary ADT (either in the form of bilateral orchiectomy or luteinizing hormone-releasing hormone agonists) in two university hospitals from year 2000 to 2009. Only patients with radiological or histological evidence of bone metastases were included. Patients who were given maximal androgen blockade were included, whereas patients who had prior radical prostatectomy or radical radiotherapy were excluded from our study. Patients’ and disease characteristics including age, Gleason score, clinical T-stage, baseline PSA and PSA nadir level were recorded. Survival outcomes including progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) were reviewed. Baseline PSA was defined as the PSA level before the initiation of ADT. PSA nadir was defined as the lowest PSA level achieved after the initiation of ADT. Progression was defined as at least two serial rises in PSA (taken at least one week apart) from its nadir level. Initiation of any secondary hormone treatment for rising PSA was also considered as a progression event. PSA nadir level was categorized into two groups: ≤1.0 and >1.0 ng/mL. The associations of PSA nadir with PFS, CSS and OS in the two PSA nadir groups were analyzed with Kaplan–Meier method, and the significance was determined by log-rank test. The
© 2014 Wiley Publishing Asia Pty Ltd
JYC Teoh et al.
prognostic significance of PSA nadir was further analyzed with univariate and multivariate Cox regression analyses. The median PFS, CSS and OS, and the 1-year to 5-year survival rates of the two PSA nadir groups were presented. A P-value of 1.0 ng/mL group. Upon univariate Cox regression analyses (Table 2), a higher Gleason score was associated with worse PFS (Gleason score 8–10, hazard ratio [HR] 1.79, 95% confidence interval [CI] 1.13–2.86, P = 0.014) and CSS (Gleason score 7, HR 2.25, 95% CI 1.05–4.84, P = 0.038; Gleason score 8–10, HR 2.30, 95% CI
Table 1
Patients’ and disease characteristics of the cohort
Mean age (years) Mean follow-up (months) Gleason score ≤6 7 8–10 Clinical T-stage 1 2 3/4 Median baseline PSA (ng/mL) PSA nadir groups (ng/mL) ≤1.0 >1.0 Median PSA nadir (ng/mL)
Value
Percentage
74.2 ± 8.3 44.8 ± 33.7
– –
– – –
10.6 22.2 67.2
– – – 212.3
8.1 48.3 42.6 –
– – 2.0
34.1 65.9 –
PSA, prostate-specific antigen.
Asia-Pac J Clin Oncol 2014
3
Survival in relation to PSA nadir
1.14–4.67, P = 0.021). A higher PSA nadir was associated with shorter PFS (HR 1.90, 95% CI 1.46– 2.47, P < 0.001), CSS (HR 1.73, 95% CI 1.16–2.56, P = 0.007) and OS (HR 1.97, 95% CI 1.53–2.53, P < 0.001). Upon multivariate analyses (Table 3), a higher PSA nadir was associated with shorter PFS (HR 1.86, 95% CI 1.35–2.56, P < 0.001) and OS (HR 1.77, 95% CI 1.20–2.41, P < 0.001). A higher PSA nadir also appeared to be associated with shorter CSS (HR 1.60, 95% CI 0.98–2.64, P = 0.063). Upon the end of the follow-up period, 74% of the patients developed disease progression after initial ADT. The median PFS were 15 and 10 months in the PSA nadir groups of ≤1.0 and >1.0 ng/mL, respectively. In the ≤1.0 ng/mL group, the PFS rates dropped gradually from 64% at 1 year to 10% at 5 years. The 1-year PFS rate in the >1.0 ng/mL group was 40%, which then dropped to 5% at 3 years and finally reached 2% at 5 years (Table 4). Concerning the CSS (Table 4), the median survival rates were 42 and 27 months in the PSA nadir groups of ≤1.0 and >1.0 ng/mL, respectively. The 1-year CSS rates (87% and 85%) in the PSA nadir groups of ≤1.0 and >1.0 ng/mL were similar. The CSS rates of the >1.0 ng/mL group then dropped relatively quicker than the ≤1.0 ng/mL group. The 5-year CSS rates were 53% and 28% in the PSA nadir groups of ≤1.0 and >1.0 ng/ mL, respectively. Concerning the OS (Table 4), the median survival were 41 and 24 months in the PSA nadir groups of ≤1.0 and >1.0 ng/mL, respectively. The OS rate in the ≤1.0 ng/mL group was 84% at 1 year, which then dropped gradually down to 45% at 5 years; the OS rate in the >1.0 ng/mL group was 77% at 1 year, which then dropped relatively quicker down to 19% at 5 years.
DISCUSSION
Figure 1 Kaplan–Meier analyses on the survival outcomes between the two prostate-specific antigen nadir groups. ADT, androgen deprivation therapy. ( ) 1.0; ( ) 1.0 – censored.
Asia-Pac J Clin Oncol 2014
ADT has been widely accepted in treating advanced prostate cancer. It has shown that ADT can reduce the incidence of pathological fracture, spinal cord compression, bilateral ureteral obstruction and extra-skeletal metastases.4 It is important to investigate for predictive factors of survival in order to identify those patients with high-risk disease. This is especially important for those with good general condition as other forms of systemic therapy can be considered early on. As evidence on the role of PSA nadir in Chinese prostate cancer patients with bone metastases following primary ADT is limited, we conducted this study to investigate the prog-
© 2014 Wiley Publishing Asia Pty Ltd
4
Table 2
JYC Teoh et al.
Univariate Cox regression analyses of clinicopathological factors predicting survival outcomes Progression-free survival
Age Gleason score ≤6 7 8–10 Clinical T-stage 1 2 3/4 Baseline PSA PSA nadir (ng/mL) ≤1.0 >1.0
Cancer-specific survival
Overall survival
HR (95% CI)
P-value
HR (95% CI)
P-value
HR (95% CI)
P-value
1.00 (0.98–1.01)
0.846
1.00 (0.98–1.02)
0.864
1.01 (0.99–1.03)
0.202
1.00 (Ref) 1.34 (0.80–2.26) 1.79 (1.13–2.86)
– 0.265 0.014
1.00 (Ref) 2.25 (1.05–4.84) 2.30 (1.14–4.67)
– 0.038 0.021
1.00 (Ref) 1.04 (0.66–1.63) 1.37 (0.92–2.05)
– 0.875 0.124
1.00 (Ref) 1.31 (0.84–2.03) 1.28 (0.82–1.99) 1.00 (1.00–1.00)
– 0.230 0.277 0.224
1.00 (Ref) 0.95 (0.51–1.78) 0.98 (0.52–1.84) 1.00 (1.00–1.00)
– 0.875 0.953 0.031
1.00 (Ref) 0.92 (0.60–1.41) 0.95 (0.62–1.46) 1.00 (1.00–1.00)
– 0.703 0.806 0.036
1.00 (Ref) 1.90 (1.46–2.47)
– 0.2 ng/mL was associated with shorter OS (HR 3.73, 95% CI 1.54–9.03, P = 0.003). In contrast to those patients with localized disease receiving curative treatment, either in the form of radical prostatectomy or radiotherapy, it is more difficult for metastatic prostate cancer patients receiving primary ADT to achieve an undetectable PSA nadir level. We decided to use 1.0 ng/mL as the cut-off level to categorize our patients into two groups for further analyses in our study. In our locality, bone scan is the usual standard workup for metastatic disease, and other imaging modalities including computed tomography scan, magnetic resonance imaging and positron emission tomography scan were not routinely performed. As this might affect the accuracy of the rates of lymph node or other distant metastases in our cohort, we decided to include only patients with bone metastases in our study. This would potentially yield more accurate results on this relatively homogeneous group of patients. In our study, a higher PSA nadir level was associated with shorter PFS, CSS and OS upon Kaplan–Meier analyses. A higher PSA nadir level was associated with shorter PFS (P < 0.001), CSS (P = 0.007) and OS (P < 0.001) upon univariate Cox regression analyses. Upon multivariate Cox regression analyses, although the association became insignificant for CSS (P = 0.063), the associations remained statistically significant for both PFS (P < 0.001) and OS (P < 0.001). We believe that PSA nadir is a promising prognostic indicator in metastatic prostate cancer patients receiving primary ADT. Up to 74% of our cohort had PSA progression after primary ADT and this is similar to that quoted in the literature.20 To our knowledge, this is the largest series investigating the prognostic significance of PSA nadir in Chinese prostate cancer patients with bone metastases following primary ADT. Due to the limited literature available in the Chinese population, our study aimed to provide Chinese-specific results that would be more applicable in managing prostate cancer in our locality. The strength of our study is the homogeneity of the patients included. The prognostic significance of PSA nadir shown by our
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study is important in deciding the best treatment strategy in patients with disease progression after primary ADT; the survival data presented may translate into clinical use and are useful in counseling this group of patients. The main limitation is the retrospective nature of our study. Without a standard treatment and follow-up protocol, the data collected may not accurately reflect the situation. Serum testosterone level was not tested routinely in our patients, in which an adequate castration level could not be ascertained. The lack of information on the use of chemotherapy is another potential confounding factor that may affect our results. Apart from PFS, CSS and OS, clinical progression-free survival is another important aspect to look into. Unfortunately, due to the retrospective nature of our study, we do not have accurate information on the clinical progression in our cohort, and further studies are necessary to look into this. Moreover, other PSA kinetic parameters such as time to PSA nadir and PSA doubling time from nadir should be investigated. These parameters may possibly help identify patients with high-risk disease and provide useful information in deciding the best treatment strategy. Nevertheless, a comprehensive evaluation on the role of PSA nadir as a survival predictor for any additional treatment would require a high quality study in the form of randomized controlled trial. Further prospective trials with larger cohort size will be necessary in the future, especially in the context of Chinese population.
CONCLUSIONS In prostate cancer patients with bone metastases receiving primary ADT, a higher PSA nadir level is associated with shorter PFS, CSS and OS. The survival data may serve as a reference in deciding the best treatment strategy in patients with disease progression after primary ADT.
REFERENCES 1 Steinberg GD, Carter BS, Beaty TH, Childs B, Walsh PC. Family history and the risk of prostate cancer. Prostate 1990; 17 (4): 337–47. 2 Gronberg H, Damber L, Damber JE. Familial prostate cancer in Sweden. A nationwide register cohort study. Cancer 1996; 77 (1): 138–43. 3 Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. J Urol 2002; 168 (1): 9–12.
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4 Sharifi N, Gulley JL, Dahut WL. Androgen deprivation therapy for prostate cancer. JAMA 2005; 294 (2): 238– 44. 5 Shahinian VB, Kuo YF, Freeman JL, Orihuela E, Goodwin JS. Increasing use of gonadotropin-releasing hormone agonists for the treatment of localized prostate carcinoma. Cancer 2005; 103 (8): 1615–24. 6 Keizman D, Huang P, Antonarakis ES et al. The change of PSA doubling time and its association with disease progression in patients with biochemically relapsed prostate cancer treated with intermittent androgen deprivation. Prostate 2011; 71 (15): 1608–15. 7 Stewart AJ, Scher HI, Chen MH et al. Prostate-specific antigen nadir and cancer-specific mortality following hormonal therapy for prostate-specific antigen failure. J Clin Oncol 2005; 23 (27): 6556–60. 8 Rodrigues NA, Chen MH, Catalona WJ, Roehl KA, Richie JP, D’Amico AV. Predictors of mortality after androgendeprivation therapy in patients with rapidly rising prostatespecific antigen levels after local therapy for prostate cancer. Cancer 2006; 107 (3): 514–20. 9 Benaim EA, Pace CM, Lam PM, Roehrborn CG. Nadir prostate-specific antigen as a predictor of progression to androgen-independent prostate cancer. Urology 2002; 59 (1): 73–8. 10 Choueiri TK, Xie W, D’Amico AV et al. Time to prostatespecific antigen nadir independently predicts overall survival in patients who have metastatic hormone-sensitive prostate cancer treated with androgen-deprivation therapy. Cancer 2009; 115 (5): 981–7. 11 Huang SP, Bao BY, Wu MT et al. Impact of prostatespecific antigen (PSA) nadir and time to PSA nadir on disease progression in prostate cancer treated with androgen-deprivation therapy. Prostate 2011; 71 (11): 1189–97. 12 Huang SP, Bao BY, Wu MT et al. Significant associations of prostate-specific antigen nadir and time to prostatespecific antigen nadir with survival in prostate cancer patients treated with androgen-deprivation therapy. Aging Male 2012; 15 (1): 34–41. 13 Soga N, Arima K, Sugimura Y. Undetectable level of prostate specific antigen (PSA) nadir predicts PSA biochemical failure in local prostate cancer with delayed-combined androgen blockade. Jpn J Clin Oncol 2008; 38 (9): 617– 22. 14 Hori S, Jabbar T, Kachroo N, Vasconcelos JC, Robson CN, Gnanapragasam VJ. Outcomes and predictive factors for biochemical relapse following primary androgen deprivation therapy in men with bone scan negative prostate cancer. J Cancer Res Clin Oncol 2011; 137 (2): 235– 41. 15 Morote J, Trilla E, Esquena S, Abascal JM, Reventos J. Nadir prostate-specific antigen best predicts the progression to androgen-independent prostate cancer. Int J Cancer 2004; 108 (6): 877–81.
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16 Kwak C, Jeong SJ, Park MS, Lee E, Lee SE. Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. J Urol 2002; 168 (3): 995–1000. 17 Kitagawa Y, Ueno S, Izumi K et al. Nadir prostate-specific antigen (PSA) level and time to PSA nadir following primary androgen deprivation therapy as independent prognostic factors in a Japanese large-scale prospective cohort study (J-CaP). J Cancer Res Clin Oncol 2014; 140 (4): 673–9. 18 Park YH, Hwang IS, Jeong CW, Kim HH, Lee SE, Kwak C. Prostate specific antigen half-time and prostate specific antigen doubling time as predictors of response to andro-
Asia-Pac J Clin Oncol 2014
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gen deprivation therapy for metastatic prostate cancer. J Urol 2009; 181 (6): 2520–4, discussion 2525. 19 Miyamoto S, Ito K, Miyakubo M et al. Impact of pretreatment factors, biopsy Gleason grade volume indices and post-treatment nadir PSA on overall survival in patients with metastatic prostate cancer treated with step-up hormonal therapy. Prostate Cancer Prostatic Dis 2012; 15 (1): 75–86. 20 Sasaki T, Onishi T, Hoshina A. Nadir PSA level and time to PSA nadir following primary androgen deprivation therapy are the early survival predictors for prostate cancer patients with bone metastasis. Prostate Cancer Prostatic Dis 2011; 14 (3): 248–52.
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