Prognostic value of alkaline phosphatase in hormone-sensitive prostate cancer: a systematic review and meta-analysis
verfasst von:
Keiichiro Mori, Florian Janisch, Mehdi Kardoust Parizi, Hadi Mostafaei, Ivan Lysenko, Dmitry V. Enikeev, Shoji Kimura, Shin Egawa, Shahrokh F. Shariat
To assess the prognostic value of alkaline phosphatase in patients with hormone-sensitive prostate cancer.
Methods
A systematic review and meta-analysis was performed using the PUBMED, Web of Science, Cochrane Library, and Scopus in April 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared hormone-sensitive prostate cancer patients with high vs. low alkaline phosphatase to determine its predictive value for overall survival, cancer-specific survival, and progression-free survival. We performed a formal meta-analysis of these outcomes.
Results
42 articles with 7938 patients were included in the systematic review and 28 studies with 5849 patients for the qualitative assessment. High alkaline phosphatase was associated with worse overall survival (pooled HR 1.72; 95% CI 1.37−2.14) and progression-free survival (pooled HR 1.30; 95% CI 1.10−1.54). In subgroup analyses of patients with “high-volume” and “low-volume”, alkaline phosphatase was associated with the overall survival (pooled HR 1.41; 95% CI 1.21−1.64 and pooled HR 1.64; 95% CI, 1.06−2.52, respectively).
Conclusions
In this meta-analysis, elevated serum levels of alkaline phosphatase were associated with an increased risk of overall mortality and disease progression in patients with hormone-sensitive prostate cancer. In contrast, those were not associated with an increased risk of cancer-specific mortality. Alkaline phosphatase was independently associated with overall survival in both patients with “high-volume” and “low-volume” hormone-sensitive prostate cancer. Alkaline phosphatase may be useful for being integrated into prognostic tools that help guide treatment strategy, thereby facilitating the shared decision making process.
Hinweise
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Introduction
Prostate cancer (PC) is not only the most common solid cancer, but also the second most common cause of cancer-related death in men [1]. Following the results of the CHAARTED trial and the LATITUDE trial, the treatment of patients with metastatic hormone-sensitive prostate cancer (HSPC) has changed substantially in the recent years [2, 3]. However, systemic therapy based on androgen deprivation remains the standard primary treatment strategy in patients with metastatic HSPC. Despite adequate therapy, the disease eventually progresses to a castration-resistant prostate cancer (CRPC) [4]. To improve PC outcomes, prognostic tools have been developed to help in the daily clinical decision making and patient counselling [5‐8]. These tools include standard clinical features and biomarkers [9], such as alkaline phosphatase (ALP) in patients with CRPC, but not yet in patients with HSPC.
ALP is a glycoprotein derived from bones, liver, kidney, or placenta that has been shown to be elevated and of prognostic value for various malignancies [10‐13]. In PC, ALP has been shown to be of prognostic value in CRPC-reflecting disease outcome, independent of therapy [14]. In patients with CRPC, high-baseline ALP levels have been shown to be associated with worse outcomes, including skeletal complications and decreased survival [15‐17]. Moreover, elevated ALP was also been shown to be correlated with the extent of metastatic bone disease [17, 18]. Serum ALP is deemed a simple and inexpensive test that could serve as an objective prognostic parameter that helps improve daily oncologic clinical practice, plan follow-up, and counsel regarding outcomes, thus facilitating the shared decision making process with the patient. Unfortunately, to date, the prognostic value of ALP in HSPC remains insufficiently investigated.
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The aim of the current study was to summarize the available data to test the hypothesis that ALP has a strong prognostic value for oncologic outcomes in HSPC patients. To this end, we performed a systematic review and a meta-analysis.
Materials and methods
Search strategy
This systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement [19]. We searched the electronic databases PUBMED, Web of Science, Cochrane Library and Scopus on April 2019, investigating the prognostic value of ALP in HSPC.
After the first screening based on study title and abstract, all papers were assessed based on full text and excluded with reasons when inappropriate; a further check of the appropriateness of the papers based on full text revision which was performed after the data extraction. Two investigators carried out this process independently. Disagreements were resolved by a consensus meeting with a third investigator. The following keywords were used in our search strategy: (prostate cancer OR prostate carcinoma OR prostate tumor OR prostatic carcinoma OR prostatic cancer OR prostatic tumor NOT resistant) AND (Alkaline Phosphatase OR ALP) AND (survival OR outcome OR prognostic OR mortality OR progression OR recurrence OR OS OR CSS OR PFS OR RFS OR MFS). The primary outcome of interest was overall survival (OS) and secondary outcomes were cancer-specific survival (CSS) and progression-free survival (PFS).
Inclusion criteria and exclusion criteria
Studies were included if they investigated whether patients with high ALP treated for HSPC (patients) who had received systemic therapy (intervention) as compared to those who had low ALP (comparison) to assess the independent predictive value of ALP on OS, CSS, and PFS (outcome) utilizing multivariate Cox regression analysis (study design) in nonrandomized observational, or randomize or cohort studies. We excluded reviews, letters, editorials, meeting abstracts, replies from author, case reports, and articles not published in English. In case of duplicate publications, either the higher quality or the most recent publication was selected. References of included manuscripts were scanned for additional studies of interest.
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Data extraction
Two investigators independently extracted the information from the included articles. The information contained the following characteristics: first author’s name, publication year, recruitment country, period of patient recruitment, number of patients, age, study design, disease stage, therapy type, oncological outcome, follow-up duration, conclusion, and ALP cut-off. Subsequently, the hazard ratios (HR) and 95% confidence intervals (CI) of ALP associated with each of the outcomes were retrieved. The HRs were extracted from the multivariate analyses. All discrepancies regarding data extraction were resolved by consensus with a third investigator.
Quality assessment
The Newcastle–Ottawa Scale (NOS) was used to assess the quality of the included studies according to the Cochrane Handbook for systematic reviews of interventions for included non-randomized studies [20, 21]. The scale focuses on the three factors: Selection (1−4), Comparability (1−2) and Exposure (1−3). The total score ranges from 0 (lowest) to 9 (highest). The main confounders were identified as the important prognostic factors of OS, CSS, and PFS. The presence of confounders was determined by consensus and review of the literature. We identified as “high-quality” choices those with scores more than 6.
Statistical analyses
We performed a forest plot to assess the HRs from the multivariate analyses of individual studies and obtained a summary HR of the value of ALP on OS, CSS, and PFS. Disease progression includes symptomatic or radiographic or biochemical progression in this analysis. Studies with Kaplan–Meier log-rank, univariate Cox proportional hazard regression, or general logistic regression analyses were not considered for the meta-analysis. In case there were only HR and P value, we calculated 95% CI [22, 23]. We also performed subgroup analyses in HSPC patients with “high-volume” and “low-volume” disease. We classified as low-volume (lesions < 4 sites and within pelvis–vertebral column) or high-volume disease (lesions ≥ 4 sites and at least one lesion beyond the pelvis–vertebral column) according to the CHAARTED classification [2]. Again, of all the HSPC patients from the studies providing information on EOD scores or Soloway scores, those with EOD scores 2 or higher or those with Soloway scores 2 or higher were defined as high-volume disease [24]. With high-volume disease thus defined, all studies in which those with high-volume disease accounted for 60% or more or less than 60% of all patients were included for the current analysis as “high-volume disease” and “low-volume disease” studies, respectively.
Heterogeneity among the outcomes of the included studies in this meta-analysis was evaluated using Cochrane Q test and I2 statistic. Significant heterogeneity was indicated by a P < 0.05 in Cochrane Q tests and a ratio > 50% in I2 statistics, which led to the use of random-effect models. We used fixed effect models for calculation of pooled HRs for non-heterogeneous results [25‐27]. Publication bias was assessed by funnel plots. Statistical analyses were performed using Stata/MP 14.2 (Stata Corp., College Station, TX); statistical significance level was set at P < 0.05.
Results
Study selection and characteristics
Our initial search identified 2245 records. After removal of duplicates, 2016 remained (Fig. 1). After screening of the titles and abstracts, 1816 articles were excluded. Then we assessed 200 full texts for further selection. After selection, 42 articles with 7938 patients were included in the systematic review and 28 studies with 5849 patients for qualitative meta-analysis [28‐69]. The baseline characteristics of the 42 studies are outlined in Table 1. All included studies were published between 1995 and 2019 with 15 being from Europe, and 27 from Asia. Median age ranged from 63 to 77 years, 10 studies included non-metastatic HSPC. Studies were heterogeneous regarding cut-off value for ALP ranging from 67 to 620 for OS, from 115 to 683.4 for CSS, and from 114.56 to 400 for PFS; follow-up ranged from 14.4 to 156 months.
Table 1
Study characteristics of 42 studies
Author
Year
Country
Recruitment period
N
Age
Design
Metastasis
Treatment
Outcome
Follow up (month)
Conclusion
Cut off (IU/L)
NOS
Reynard
1995
UK
1986–1990
85
71
P
M1
E
OS
NR
P
UNL
6
Vasalainen
1995
Finland
1971–1992
188
71.5
R
M0, M1
E
OS
156
P
UNL
6
Stokkel
1997
Netherland
1990–1995
124
71
R
M0
E, P, R
OS, PFS
41
N
NR
6
Furuya
1998
Japan
1986–1993
139
73.6
R
M1
E
CSS
36.9
N
NR
7
Akimoto
1999
Japan
NR
48
71.8
R
M1
E
CSS
32
N
NR
7
Nakashima
2000
Japan
NR
114
NR
R
M1
E
OS
NR
N
620
6
Kwak
2002
Korea
1991–1997
151
67.7
R
M0, M1
E
OS
39
P
115
7
Pelger
2002
Netherland
NR
233
75
R
M0, M1
E
PFS
NR
P
NR
7
Furuya
2003
Japan
1990–1999
59
72.9
R
M1
E
CSS
25.3
N
UNL
6
Noguchi
2003
Japan
1994–2000
56
72
R
M1
E
CSS
32
P
467
5
Yashi
2003
Japan
NR
70
72
R
M1
E
PFS
27.4
N
400
7
Jung
2004
Germany
1998–2001
117
66
R
M0, M1
E
OS
36.1
N
129
6
Brasso
2006
Denmark
1993–1996
153
72
P
M1
E
OS
59
P
Continuous
7
Salminen
2006
Finland
NR
84
67
R
M0, M1
E
OS
52
P
227
6
Saito
2007
Japan
1992–2004
241
72.3
R
M1
NR
OS
31
P
500
7
Robinson
2008
Sweden
1992–1997
697
72.8
P
M1
E
CSS
37
P
UNL
7
Jeong
2009
Korea
1987–1995
295
69.7
R
M0, M1
E
OS, CSS
39
P
115
7
Lein
2009
Germany
2002–2005
117
NR
P
M1
E,C
PFS
NR
N
NR
6
Mikkola
2009
Finland
1990–1994
142
72
P
M1
E
OS
NR
P
180
6
Kamiya
2010
Japan
2002–2008
58
69
R
M1
E
CSS
35
N
683.4
6
yamada
2010
Japan
1998–2006
104
74
R
M1
E
CSS
43
N
UNL
7
Jung
2011
Germany
2002–2005
52
68
R
M1
E
OS
49
N
67
8
Miyamoto
2011
Japan
1992–2002
94
72.5
R
M1
E
OS
38.8
P
220
7
He
2012
China
1997–2009
115
72
R
M1
E
OS
26.8
P
NR
6
Tsuchiya
2013
Japan
1980–2008
215
72
R
M1
E
CSS
37
P
350
7
Nozawa
2014
Japan
2008–2010
52
72
P
M1
E
OS, PFS
41.6
P
300
5
Gravis
2015
France
2004–2008
385
63
P
M1
E, C
OS
58.3
P
UNL
6
Koo
2015
Korea
2002–2012
248
NR
R
M1
E
CSS, PFS
39.9
P
200
7
Mohammed
2015
Saudi Arabia
2011–2015
71
72
R
M1
NR
CSS
14.4
P
NR
6
Kato
2016
Japan
2002–2012
150
73
R
M1
E
OS
38
N
398
7
Klaff
2016
Sweden
1992–1997
319
NR
P
M1
E
OS
112.5
N
1.25xUNL
7
Klaff
2016
Sweden
1992–1997
483
NR
P
M1
E
OS
63.3
P
1.25xUNL
7
Lv
2016
China
2009–2014
168
72
R
M1
E
PFS
22
P
114.56
6
Pan
2016
China
2009–2012
155
NR
P
M1
E
OS, PFS
38
N
220
7
Peng
2016
China
1997–2012
113
64
R
M1
E
OS
41
P
150
7
Josefsson
2017
Sweden
2012–2015
40
77
P
M1
E
PFS
NR
P
Continuous
6
Wang
2017
China
2004–2015
438
70
R
M0
P
PFS
52
N
Continuous
7
Buelens
2018
Belgium
2014–2018
113
70
P
M1
E,C
OS
20
P
UNL
6
Okamoto
2018
Japan
2005–2017
339
72
R
M1
E
OS, CSS, PFS
26
N
322
7
Sato
2018
Japan
2000–2015
60
72
R
M1
E
OS, PFS
34
P
UNL
7
Zhao
2018
China
2011–2016
449
NR
R
M1
E
OS, PFS
50
P
UNL
7
Miyake
2019
Japan
2010–2017
437
NR
R
M1
E
OS
46.5
P
400
7
Shimodaira
2019
Japan
1999–2012
167
74.8
R
M0, M1
E
CSS
54.3
P
350
6
C chemotherapy, CSS cancer-specific survival, E endocrine therapy, N (outcome): negative, NOS Newcastle–Ottawa Scale, NR not reported, OS overall survival, P (design) prospective, P (outcome) positive, P (treatment): prostatectomy, PFS progression-free survival, R (design) retrospective, R (treatment) radiotherapy, UNL upper normal limit
×
Meta-analysis
Association of ALP with OS in HSPC
Sixteen studies including 3747 patients provided data on the association of ALP with OS in HSPC. The forest plot (Fig. 2a) showed that ALP was significantly associated with OS in HSPC (pooled HR 1.72; 95% CI 1.37 − 2.14; z = 4.76). The Cochrane Q test (χ2 = 85.73; P = 0.000) and I2 test (I2 = 81.3%) showed significant heterogeneity. The funnel plot identified nine studies over the pseudo 95% CI (Fig. 2a).
×
Association of ALP with CSS in HSPC
Ten studies including 2225 patients provided data on the association of ALP with CSS in HSPC. The forest plot (Fig. 2b) showed that ALP was not significantly associated with CSS in HSPC (pooled HR 1.00; 95% CI 1.00–1.01; z = 1.55). The Cochrane Q test (χ2 = 80.97; P = 0.000) and I2 test (I2 = 88.9%) showed significant heterogeneity. The funnel plot identified four studies over the pseudo 95% CI (Fig. 2b).
Association of ALP with PFS in HSPC
Seven studies including 1547 patients provided data on the association of ALP with PFS in HSPC. The forest plot (Fig. 2c) showed that ALP was significantly associated with PFS in HSPC (pooled HR 1.30; 95% CI 1.10−1.54; z = 3.04). The Cochrane Q test (χ2 = 40.49; P = 0.000) and I2 test (I2 = 85.2%) showed significant heterogeneity. The funnel plot identified four studies over the pseudo 95% CI (Fig. 2c).
Association of ALP with OS in HSPC with “high volume”
Five studies including 1509 patients provided data on the association of ALP with OS in HSPC with “high-volume” disease. The forest plot (Fig. 3a) showed that ALP was significantly associated with OS in HSPC with “high-volume” disease (pooled HR 1.41; 95% CI 1.21−1.64; z = 4.47). The Cochrane Q test (χ2 = 7.25; P = 0.123) and I2 test (I2 = 44.8%) showed no significant heterogeneity. The funnel plot identified no studies over the pseudo 95% CI (Fig. 3a).
×
Association of ALP with OS in HSPC with “low volume”
Six studies including 1039 patients provided data on the association of ALP with OS in HSPC with “low-volume” disease. The forest plot (Fig. 3b) showed that ALP was significantly associated with OS in HSPC with “low-volume” disease (pooled HR 1.64; 95% CI 1.06−2.52; z = 2.25). The Cochrane Q test (χ2 = 22.10; P = 0.001) and I2 test (I2 = 77.4%) showed significant heterogeneity. The funnel plot identified three studies over the pseudo 95% CI (Fig. 3b).
Discussion
In this systematic review and meta-analysis, we investigated the prognostic value of ALP in HSPC by assessing its impact on PFS, CSS, and OS. We found that the HSPC patients with elevated ALP have significantly worse OS and PFS compared to their counterparts with normal ALP levels. In other words, pre-treatment ALP values may be a useful biomarker in the choice of treatment, even in early metastatic PC.
The prognostic value of ALP has been shown in various solid malignancies with bone metastasis [11‐13]. However, while there is a biological rationale underlying this association, the exact mechanism remains unclear. A potential explanation is that when cancer starts to metastasize, ALP reflects bone turnover, osteoblast activity, and osteoid formation in the adjacent bone tissues [70]. Thus, ALP may be an indicator of bone metastatic tumor load. Accordingly, ALP has been shown to be elevated in cancer patients with bone metastasis, as the current literature shows, ALP is already among the biomarkers included in the tools used for prognosticating outcomes in CRPC patients [5‐8].
Interestingly, ALP was significantly associated with worse OS in metastatic HSPC patients not only with “high-volume” disease, but also with “low-volume” disease, suggesting that ALP is an indirect sensitive measure of metastatic tumor burden which could not be captured by conventional imaging. It is likely that the elevated ALP reflects micro metastases despite negative findings on conventional imaging. Although few studies have assessed this patient subgroup, ALP could be used to select patients who may benefit more from intensive therapy such as upfront docetaxel or abiraterone in addition to standard androgen deprivation therapy. Moreover, ALP could also be used as a response/monitoring marker for these therapies as well as bone-targeting therapies such as bisphosphonate.
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Despite showing a strong association of ALP with mortality and progression in HSPC patients, this systematic review and meta-analysis has some limitations. There is a reporting bias, as some studies with negative results may not have been published. Further, many included studies were retrospective, leading to a patient selection bias. Second, unknown pretreatment conditions (i.e., physical conditions, comorbidities, obstructive jaundice, bone disease, hyperthyroidism and hepatitis, medication, and life-style habits) could have altered ALP values leading to a systematic bias. Third, heterogeneity was detected for OS, CSS, and PFS analyses limiting the value of these results. Although the random effect model takes into account the heterogeneity among studies, the conclusions should be interpreted with caution. Fourth, there is no established cut-off value for ALP among the included studies; most investigators chose the cut-off based on the statistical methods assessing for the highest sensitivity and specificity, using the upper limit of normal, or using literature predefined ALP cut-offs. Only three studies investigated ALP as a continuous variable. Regardless of these limitations, ALP is a fast and readily available biomarker. Well-designed prospective studies with longer follow-up are needed to validate the prognostic value of ALP and its potential value in risk stratification of patients with HSPC using clinical decision-analytical tools.
Conclusions
In this meta-analysis, high serum ALP was associated with an increased risk of overall mortality and disease progression in patients with HSPC. In contrast, high serum ALP was not associated with an increased risk of cancer-specific mortality. Furthermore, ALP was an independent risk factor for OS in HSPC patients with both “high-volume” and “low-volume” metastatic disease. ALP may be useful for clinical decision making regarding treatment selection, as well as for patient counselling. However, considering the limitations including heterogeneity, the conclusions should be interpreted with caution.
Acknowledgements
Open access funding provided by Medical University of Vienna.
Compliance with ethical standards
Conflict of interest
None of the authors have conflicts of interest to disclose.
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