PURPOSE: 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.

Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Urology Medical University of Hamburg Hamburg Germany

Department of Urology Medical University of Vienna Währinger Gürtel 18 20 1090 Vienna Austria

Department of Urology Shariati Hospital Tehran University of Medical Sciences Teheran Iran

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Research Center for Evidence Based Medicine Tabriz University of Medical Sciences Tabriz Iran

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Siegel Rebecca L., Miller Kimberly D., Jemal Ahmedin. Cancer statistics, 2018. CA: A Cancer Journal for Clinicians. 2018;68(1):7–30. PubMed

Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. New Engl J Med. 2015;373(8):737–746. doi: 10.1056/NEJMoa1503747. PubMed DOI PMC

Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. New Engl J Med. 2017;377(4):352–360. doi: 10.1056/NEJMoa1704174. PubMed DOI

Kluth LA, Shariat SF, Kratzik C, et al. The hypothalamic-pituitary-gonadal axis and prostate cancer: implications for androgen deprivation therapy. World J Urol. 2014;32(3):669–676. doi: 10.1007/s00345-013-1157-5. PubMed DOI

Chi KN, Kheoh T, Ryan CJ, et al. A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel. Ann Oncol. 2016;27(3):454–460. doi: 10.1093/annonc/mdv594. PubMed DOI PMC

Halabi S, Lin CY, Kelly WK, et al. Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2014;32(7):671–677. doi: 10.1200/jco.2013.52.3696. PubMed DOI PMC

Armstrong AJ, Garrett-Mayer E, de Wit R, et al. Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer. Clin Cancer Res. 2010;16(1):203–211. doi: 10.1158/1078-0432.ccr-09-2514. PubMed DOI

Shariat SF, Kattan MW, Vickers AJ, et al. Critical review of prostate cancer predictive tools. Fut Oncol (Lond Engl) 2009;5(10):1555–1584. doi: 10.2217/fon.09.121. PubMed DOI PMC

Shariat SF, Semjonow A, Lilja H, et al. Tumor markers in prostate cancer I: blood-based markers. Acta Oncol (Stockholm, Sweden) 2011;50(Suppl 1):61–75. doi: 10.3109/0284186x.2010.542174. PubMed DOI PMC

Pochanugool L, Subhadharaphandou T, Dhanachai M, et al. Prognostic factors among 130 patients with osteosarcoma. Clin Orthop Relat Res. 1997;345:206–214. doi: 10.1097/00003086-199712000-00030. PubMed DOI

Liu F, Zhao J, Xie J, et al. Prognostic risk factors in patients with bone metastasis from colorectal cancer. Tumour Biol. 2016 doi: 10.1007/s13277-016-5465-4. PubMed DOI

Lim SM, Kim YN, Park KH, et al. Bone alkaline phosphatase as a surrogate marker of bone metastasis in gastric cancer patients. BMC Cancer. 2016;16:385. doi: 10.1186/s12885-016-2415-x. PubMed DOI PMC

Huang P, Lan M, Peng AF, et al. Serum calcium, alkaline phosphotase and hemoglobin as risk factors for bone metastases in bladder cancer. PLoS ONE. 2017;12(9):e0183835. doi: 10.1371/journal.pone.0183835. PubMed DOI PMC

Bitting RL, Armstrong AJ. Potential predictive biomarkers for individualizing treatment for men with castration-resistant prostate cancer. Cancer J (Sudbury, Mass) 2013;19(1):25–33. doi: 10.1097/PPO.0b013e31827e0b9c. PubMed DOI

Brown JE, Cook RJ, Major P, et al. Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst. 2005;97(1):59–69. doi: 10.1093/jnci/dji002. PubMed DOI

Coleman RE, Major P, Lipton A, et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol. 2005;23(22):4925–4935. doi: 10.1200/jco.2005.06.091. PubMed DOI

Armstrong AJ, Febbo PG. Using surrogate biomarkers to predict clinical benefit in men with castration-resistant prostate cancer: an update and review of the literature. Oncologist. 2009;14(8):816–827. doi: 10.1634/theoncologist.2009-0043. PubMed DOI

D'Oronzo Stella, Brown Janet, Coleman Robert. The value of biomarkers in bone metastasis. European Journal of Cancer Care. 2017;26(6):e12725. doi: 10.1111/ecc.12725. PubMed DOI

Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6(7):e1000100. doi: 10.1371/journal.pmed.1000100. PubMed DOI PMC

Stang A. Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603–605. doi: 10.1007/s10654-010-9491-z. PubMed DOI

Deeks JJ, Dinnes J, D'Amico R et al (2003) Evaluating non-randomised intervention studies. Health Technol Assess (Winchester, England) 7(27):iii-x, 1–173 PubMed

Altman DG, Bland JM. How to obtain the confidence interval from a P value. BMJ (Clin Res) 2011;343:d2090. doi: 10.1136/bmj.d2090. PubMed DOI

Altman DG, Bland JM. How to obtain the P value from a confidence interval. BMJ (Clin Res) 2011;343:d2304. doi: 10.1136/bmj.d2304. PubMed DOI

Soloway MS, Hardeman SW, Hickey D, et al. Stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. Cancer. 1988;61(1):195–202. doi: 10.1002/1097-0142(19880101)61:1<195::AID-CNCR2820610133>3.0.CO;2-Y. PubMed DOI

DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemp Clin Trial. 2007;28(2):105–114. doi: 10.1016/j.cct.2006.04.004. PubMed DOI

DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–188. doi: 10.1016/0197-2456(86)90046-2. PubMed DOI

Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–560. doi: 10.1136/bmj.327.7414.557. PubMed DOI PMC

Akimoto S, Furuya Y, Akakura K, et al. Inability of bone turnover marker as a strong prognostic indicator in prostate cancer patients with bone metastasis: comparison with the extent of disease (EOD) grade. Prostate. 1999;38(1):28–34. doi: 10.1002/(SICI)1097-0045(19990101)38:1<28::AID-PROS3>3.0.CO;2-M. PubMed DOI

Brasso K, Christensen IJ, Johansen JS, et al. Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate. 2006;66(5):503–513. doi: 10.1002/pros.20311. PubMed DOI

Buelens S, De Bleser E, Dhondt B, et al. Importance of metastatic volume in prognostic models to predict survival in newly diagnosed metastatic prostate cancer. World J Urol. 2018 doi: 10.1007/s00345-018-2449-6. PubMed DOI

Furuya Y, Akimoto S, Akakura K. Response of prostate-specific antigen after androgen withdrawal and prognosis in men with metastatic prostate cancer. Urol Int. 1998;60(1):28–32. doi: 10.1159/000030199. PubMed DOI

Furuya Y, Nagakawa O, Fuse H. Prognostic significance of changes in short-term prostate volume and serum prostate-specific antigen after androgen withdrawal in men with metastatic prostate cancer. Urol Int. 2003;70(3):195–199. doi: 10.1159/000068769. PubMed DOI

Gravis G, Boher JM, Fizazi K, et al. Prognostic factors for survival in noncastrate metastatic prostate cancer: validation of the glass model and development of a novel simplified prognostic model. Eur Urol. 2015;68(2):196–204. doi: 10.1016/j.eururo.2014.09.022. PubMed DOI

He J, Zeng ZC, Yang P, et al. Clinical features and prognostic factors for patients with bone metastases from prostate cancer. Asian J Androl. 2012;14(3):505–508. doi: 10.1038/aja.2012.24. PubMed DOI PMC

Jeong CW, Ku JH, Kwak C, et al. Chronic pulmonary disease negatively influences the prognosis of patients with advanced prostate cancer. World J Urol. 2009;27(5):643–652. doi: 10.1007/s00345-009-0375-3. PubMed DOI

Josefsson A, Linder A, Flondell Site D, et al. Circulating tumor cells as a marker for progression-free survival in metastatic castration-naïve prostate cancer. Prostate. 2017;77(8):849–858. doi: 10.1002/pros.23325. PubMed DOI

Jung K, Lein M, Stephan C, et al. Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications. Int J Cancer. 2004;111(5):783–791. doi: 10.1002/ijc.20314. PubMed DOI

Jung K, Miller K, Wirth M, et al. Bone turnover markers as predictors of mortality risk in prostate cancer patients with bone metastases following treatment with zoledronic acid. Eur Urol. 2011;59(4):604–612. doi: 10.1016/j.eururo.2010.12.006. PubMed DOI

Kamiya N, Suzuki H, Yano M, et al. Implications of serum bone turnover markers in prostate cancer patients with bone metastasis. Urology. 2010;75(6):1446–1451. doi: 10.1016/j.urology.2009.11.049. PubMed DOI

Kato Masashi, Tsuzuki Toyonori, Kimura Kyosuke, Hirakawa Akihiro, Kinoshita Fumie, Sassa Naoto, Ishida Ryo, Fukatsu Akitoshi, Kimura Tohru, Funahashi Yasuhito, Matsukawa Yoshihisa, Hattori Ryohei, Gotoh Momokazu. The presence of intraductal carcinoma of the prostate in needle biopsy is a significant prognostic factor for prostate cancer patients with distant metastasis at initial presentation. Modern Pathology. 2016;29(2):166–173. doi: 10.1038/modpathol.2015.146. PubMed DOI

Klaff R, Varenhorst E, Berglund A, et al. Clinical presentation and predictors of survival related to extent of bone metastasis in 900 prostate cancer patients. Scand J Urol. 2016;50(5):352–359. doi: 10.1080/21681805.2016.1209689. PubMed DOI

Koo KC, Park SU, Kim KH, et al. Predictors of survival in prostate cancer patients with bone metastasis and extremely high prostate-specific antigen levels. Prostate Int. 2015;3(1):10–15. doi: 10.1016/j.prnil.2015.02.006. PubMed DOI PMC

Kwak C, Jeong SJ, Park MS, et al. Prognostic significance of the nadir prostate specific antigen level after hormone therapy for prostate cancer. J Urol. 2002;168(3):995–1000. doi: 10.1097/01.ju.0000024925.67014.21. PubMed DOI

Lein M, Miller K, Wirth M, et al. Bone Turnover markers as predictive tools for skeletal complications in men with metastatic prostate cancer treated with zoledronic acid. Prostate. 2009;69(6):624–632. doi: 10.1002/pros.20917. PubMed DOI

Lv W, Shang HX, Pei XQ, et al. A simple prognostic model involving prostate-specific antigen, alkaline phosphatase and albumin for predicting the time required to progress to castration-resistant prostate cancer in patients who received androgen deprivation therapy. Int Urol Nephrol. 2017;49(1):61–67. doi: 10.1007/s11255-016-1456-z. PubMed DOI

Mikkola A, Aro J, Rannikko S, et al. Prognostic grouping of metastatic prostate cancer using conventional pretreatment prognostic factors. Scand J Urol Nephrol. 2009;43(4):265–270. doi: 10.1080/00365590902836500. PubMed DOI

Miyake H, Matsushita Y, Watanabe H, et al. Prognostic significance of time to castration resistance in patients with metastatic castration-sensitive prostate cancer. Anticancer Res. 2019;39(3):1391–1396. doi: 10.21873/anticanres.13253. PubMed DOI

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. doi: 10.1038/pcan.2011.47. PubMed DOI

Mohammed AA, El-Tanni H, Ghanem HM, et al. Impact of body mass index on clinico-pathological parameters and outcome in patients with metastatic prostate cancer. JEgypt Natl Cancer Inst. 2015;27(3):155–159. doi: 10.1016/j.jnci.2015.07.001. PubMed DOI

Nakashima J, Ozu C, Nishiyama T, et al. Prognostic value of alkaline phosphatase flare in patients with metastatic prostate cancer treated with endocrine therapy. Urology. 2000;56(5):843–847. doi: 10.1016/S0090-4295(00)00755-X. PubMed DOI

Noguchi M, Kikuchi H, Ishibashi M, et al. Percentage of the positive area of bone metastasis is an independent predictor of disease death in advanced prostate cancer. Br J Cancer. 2003;88(2):195–201. doi: 10.1038/sj.bjc.6600715. PubMed DOI PMC

Nozawa M, Hara I, Matsuyama H, et al. Significance of baseline bone markers on disease progression and survival in hormone-sensitive prostate cancer with bone metastasis. World J Urol. 2015;33(9):1263–1268. doi: 10.1007/s00345-014-1431-1. PubMed DOI

Okamoto T, Hatakeyama S, Narita S, et al. Impact of nutritional status on the prognosis of patients with metastatic hormone-naive prostate cancer: a multicenter retrospective cohort study in Japan. World J Urol. 2018 doi: 10.1007/s00345-018-2590-2. PubMed DOI

Pan X, Zhang X, Gong J, et al. The expression profile and prognostic value of SPINK1 in initially diagnosed bone metastatic prostate cancer. Prostate. 2016;76(9):823–833. doi: 10.1002/pros.23173. PubMed DOI

Pelger RC, Lycklama ANGA, Zwinderman AH, et al. The flare in alkaline phosphatase activity post-orchidectomy predicts which patient may benefit from early chemotherapy in metastatic prostate cancer. Prostate. 2002;50(2):119–124. doi: 10.1002/pros.10040. PubMed DOI

Peng B, Yang C, He J. Radiotherapy cannot prolong overall survival of young prostate cancer patients with bone metastases. J Transl Med. 2016;14:102. doi: 10.1186/s12967-016-0868-y. PubMed DOI PMC

Reynard JM, Peters TJ, Gillatt D. Prostate-specific antigen and prognosis in patients with metastatic prostate cancer–a multivariable analysis of prostate cancer mortality. Br J Urol. 1995;75(4):507–515. doi: 10.1111/j.1464-410X.1995.tb07274.x. PubMed DOI

Robinson David, Sandblom Gabriel, Johansson Robert, Garmo Hans, Stattin Pär, Mommsen Sören, Varenhorst Eberhard. Prediction of Survival of Metastatic Prostate Cancer Based on Early Serial Measurements of Prostate Specific Antigen and Alkaline Phosphatase. Journal of Urology. 2008;179(1):117–123. doi: 10.1016/j.juro.2007.08.132. PubMed DOI

Saito T, Hara N, Kitamura Y, et al. Prostate-specific antigen/prostatic acid phosphatase ratio is significant prognostic factor in patients with stage IV prostate cancer. Urology. 2007;70(4):702–705. doi: 10.1016/j.urology.2007.05.019. PubMed DOI

Salminen EK, Kallioinen MJ, Ala-Houhala MA et al (2006) Survival markers related to bone metastases in prostate cancer. Anticancer Res 26 (6 C):4879–4884 PubMed

Sato H, Narita S, Tsuchiya N, et al. Impact of early changes in serum biomarkers following androgen deprivation therapy on clinical outcomes in metastatic hormone-sensitive prostate cancer. BMC Urol. 2018;18(1):32. doi: 10.1186/s12894-018-0353-4. PubMed DOI PMC

Shimodaira K, Nakashima J, Nakagami Y, et al. Prognostic value of platelet counts in patients with metastatic prostate cancer treated with endocrine therapy. Urol J. 2019 doi: 10.22037/uj.v0i0.4735. PubMed DOI

Stokkel M, Zwinderman A, Zwartendijk J, et al. The value of pretreatment clinical and biochemical parameters in patients with newly diagnosed untreated prostate carcinoma and no indications for bone metastases on the bone scintigram. Eur J Nucl Med. 1997;24(10):1215–1220. doi: 10.1007/s002590050144. PubMed DOI

Tsuchiya N, Narita S, Inoue T, et al. Insulin-like growth factor-1 genotypes and haplotypes influence the survival of prostate cancer patients with bone metastasis at initial diagnosis. BMC Cancer. 2013 doi: 10.1186/1471-2407-13-150. PubMed DOI PMC

Vesalainen S, Lipponen P, Talja M, et al. Biochemical parameters as prognostic factors in prostatic adenocarcinoma. Acta Oncol (Stockholm, Sweden) 1995;34(1):53–59. doi: 10.3109/02841869509093639. PubMed DOI

Wang H, Fang K, Zhang J, et al. The significance of De Ritis (aspartate transaminase/alanine transaminase) ratio in predicting pathological outcomes and prognosis in localized prostate cancer patients. Int Urol Nephrol. 2017;49(8):1391–1398. doi: 10.1007/s11255-017-1618-7. PubMed DOI

Yamada Y, Naruse K, Nakamura K, et al. Investigation of risk factors for prostate cancer patients with bone metastasis based on clinical data. Exp Therap Med. 2010;1(4):635–639. doi: 10.3892/etm_00000099. PubMed DOI PMC

Yashi M, Nukui A, Kurokawa S, et al. Elevated serum progastrin-releasing peptide (31–98) level is a predictor of short response duration after hormonal therapy in metastatic prostate cancer. Prostate. 2003;56(4):305–312. doi: 10.1002/pros.10260. PubMed DOI

Zhao J, Sun G, Liao B, et al. Novel nomograms for castration-resistant prostate cancer and survival outcome in patients with de novo bone metastatic prostate cancer. BJU Int. 2018;122(6):994–1002. doi: 10.1111/bju.14398. PubMed DOI

Ren HY, Sun LL, Li HY, et al. Prognostic significance of serum alkaline phosphatase level in osteosarcoma: a meta-analysis of published data. Biomed Res Int. 2015;2015:160835. doi: 10.1155/2015/160835. PubMed DOI PMC

Combination of docetaxel versus nonsteroidal antiandrogen with androgen deprivation therapy for high-volume metastatic hormone-sensitive prostate cancer: a propensity score-matched analysis