World J Urol DOI 10.1007/s00345-014-1431-1
ORIGINAL ARTICLE
Significance of baseline bone markers on disease progression and survival in hormone‑sensitive prostate cancer with bone metastasis Masahiro Nozawa · Isao Hara · Hideyasu Matsuyama · Masayuki Iki · Kazuhiro Nagao · Tsukasa Nishioka · Takahiro Komura · Atsunobu Esa · Shigeya Uejima · Masaaki Imanishi · Yasunari Uekado · Takatoshi Ogawa · Hiroshi Kajikawa · Hirotsugu Uemura
Received: 30 July 2014 / Accepted: 23 October 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose This study evaluated the baseline patient characteristics associated with the time to biochemical progression and overall survival in patients who participated in a phase II trial on zoledronic acid combined with the initial androgen-deprivation therapy for treatment-naïve bonemetastatic prostate cancer. Methods Patients received zoledronic acid 4 mg intravenously every 4 weeks for up to 24 months, concomitantly started with bicalutamide 80 mg orally every day and goserelin acetate 10.8 mg subcutaneously every 12 weeks. Results A total of 53 Japanese patients were enrolled between July 2008 and April 2010, and 52 patients were evaluable. Median follow-up period was 41.6 months. Updated median time to biochemical progression was
25.9 months (95 % confidence interval 14.5–49.9). Higher serum bone-specific alkaline phosphatase was an independent risk factor for time to biochemical progression based on multivariate analysis (hazard ratio 6.51; 95 % confidence interval 2.71–15.62; P 249.4 ≤300 >300 ≤26.0 >26.0 ≤5.0 5.08.0 ≤50 50100
Multivariate (step-up procedure) 95 % CI
P value
Reference 0.52 Reference 1.39 Reference 1.58 Reference 2.59 Reference 1.89 Reference 1.91 Reference 2.98 Reference 1.76 Reference 2.16 Reference 6.51 Reference 0.91 2.76 Reference 3.05
(1.15–8.12)
0.025
6.82
(2.59–17.98)
300 ≤26.0 >26.0 ≤5.0 5.08.0 ≤100 >100
Reference 0.94 Reference 2.25 Reference 1.34 Reference 1.67 Reference 0.56 Reference 0.99 Reference 6.67 Reference 1.21 Reference 4.78 Reference 3.38 Reference 1.01 8.59 Reference 5.24
Multivariate (step-up procedure) 95 % CI
P value
(0.34–2.61)
0.910
(0.72–7.08)
0.165
(0.47–3.82)
0.584
(0.53–5.24)
0.383
(0.20–1.55)
0.268
(0.33–2.96)
0.983
(2.26–19.71)
0.001
(0.43–3.34)
0.721
(1.07–21.25)
0.040
(1.07–10.63)
0.037
(0.14–7.19) (1.89–39.07)
0.990 0.005
(1.77–15.47)
0.003
HR
95 % CI
P value
Reference 1.01 9.62
(0.14–7.18) (2.11–43.89)
0.991 0.003
ALP alkaline phosphatase, BAP bone-specific alkaline phosphatase, CI confidence interval, ECOG PS Eastern Cooperative Oncology Group performance status, EOD extent of bone disease, HR hazard ratio, ICTP C-terminal telopeptide of type I collagen, PSA prostate-specific antigen, uNTx urinary N-terminal cross-linked telopeptide of type I collagen
improved OS compared with placebo in metastatic CRPC [18]. Cabozantinib, a tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2, indicated improvement on bone scan in 68 % of patients with CRPC, including complete resolution in 12 % based on a phase II trial [19]. The efficacy of these new treatments against metastatic bone diseases should be theoretically promising not only for CRPC, but also for hormone-naïve PCa. There are some limitations to the current study, namely being that findings from the study are based on the data from a non-randomized single-arm phase II trial with a small number of subjects. In addition, the markers used are well known. Although no direct clinical impact can be derived because of the absence of a control arm, this study provides proof of principle that baseline bone markers may serve as predictors for biochemical progression and overall survival. We did not evaluate the association between the transition
of bone markers during treatment and clinical outcomes. In CRPC, the association between bone marker levels and clinical outcomes were stronger for on-study bone marker levels compared with baseline levels although the statistical heterogeneity in the strength of these correlations has not been reported [20]. We did not investigate the effect of treatments after disease progression with the initial ADT on OS. Docetaxel, abiraterone, enzalutamide, radium-223, and cabazitaxel can influence OS. The landscape for the treatment of hormone-naïve PCa has changed since the conception of the present study; docetaxel with ADT can improve overall survival compared with ADT alone [21], and abiraterone or enzalutamide may prove their value in this setting in the future (NCT01715285, NCT01957436) [22]. In conclusion, baseline bone markers may be useful as predictors for disease progression and survival in patients with bone metastases from treatment-naïve PCa who start treatment with ZA concomitant with ADT. Development of
13
World J Urol 1.0
p = 1.000
Probability
0.8
p = 0.005
0.6
p = 0.003 0.4
ICTP (ng/ml)
0.2
Median (95% CI) (months)
≤5.0 NA (NA-NA) >5.0, ≤8.0 NA (44.8-NA) >8.0 31.1 (19.0-NA)
0.0 0
500
1000
1500
(day)
Number at risk ICTP ≤5.0 18 ICTP >5.0, ≤8.0 17 ICTP >8.0 17
17 16 15
16 16 6
6 6 2
Fig. 2 Kaplan–Meier curves for overall survival stratified with baseline serum C-terminal telopeptide of type I collagen (ICTP) level
novel treatment strategies against metastatic bone diseases may improve the prognosis even in patients with hormonesensitive PCa. Acknowledgments The authors thank all patients and their families for participating in this study, all investigators and site staff for their contribution, and Marco De Velasco for reviewing the language. Conflict of interest The authors have no conflict of interest. Ethical standard The study was conducted according to the Declaration of Helsinki with approval from ethics committees at each institution. Written informed consent was obtained from all patients consistent with local requirements.
References 1. Coleman RE (2004) Bisphosphonates: clinical experience. Oncologist 9:14–27 2. Oefelein MG, Ricchiuti V, Conrad W, Resnick MI (2002) Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 168:1005–1007 3. Nørgaard M, Jensen AØ, Jacobsen JB, Cetin K, Fryzek JP, Sørensen HT (2010) Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol 184:162–167 4. Sathiakumar N, Delzell E, Morrisey MA et al (2011) Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US
13
medicare beneficiaries, 1999–2006. Prostate Cancer Prostatic Dis 14:177–183 5. Saad F, Gleason DM, Murray R et al (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458–1468 6. Nozawa M, Inagaki T, Nagao K et al (2014) Phase II trial of zoledronic acid combined with androgen-deprivation therapy for treatment-naïve prostate cancer with bone metastasis. Int J Clin Oncol 19:693–701 7. Scher HI, Halabi S, Tannock I et al (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. J Clin Oncol 26:1148–1159 8. Maeda H, Koizumi M, Yoshimura K, Yamauchi T, Kawai T, Ogata E (1997) Correlation between bone metabolic markers and bone scan in prostatic cancer. J Urol 157:539–543 9. Aruga A, Koizumi M, Hotta R, Takahashi S, Ogata E (1997) Usefulness of bone metabolic markers in the diagnosis and follow-up of bone metastasis from lung cancer. Br J Cancer 76:760–764 10. Cook RJ, Coleman R, Brown J et al (2006) Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res 12:3361–3367 11. Smith MR, Cook RJ, Coleman R et al (2007) Predictors of skeletal complications in men with hormone-refractory metastatic prostate cancer. Urology 70:315–319 12. Lara PN Jr, Ely B, Quinn DI et al (2014) Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: results from SWOG 0421. J Natl Cancer Inst 106: dju013 13. Berruti A, Dogliotti L, Gorzegno G et al (1999) Differential patterns of bone turnover in relation to bone pain and disease extent in bone in cancer patients with skeletal metastases. Clin Chem 45:1240–1247 14. Hollier BG, Evans K, Mani SA (2009) The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia 14:29–43 15. Lévesque JP, Helwani FM, Winkler IG (2010) The endosteal ‘osteoblastic’ niche and its role in hematopoietic stem cell homing and mobilization. Leukemia 24:1979–1992 16. Sun Y, Wang BE, Leong KG et al (2012) Androgen deprivation causes epithelial-mesenchymal transition in the prostate: implications for androgen-deprivation therapy. Cancer Res 72:527–536 17. Fizazi K, Carducci M, Smith M et al (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813–822 18. Parker C, Nilsson S, Heinrich D et al (2013) Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369:213–223 19. Smith DC, Smith MR, Sweeney C et al (2013) Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 31:412–419 20. Brown JE, Cook RJ, Major P et al (2005) Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97:59–69 21. Sweeney CJ (2006) ECOG: CHAARTED–ChemoHormonal therapy versus androgen ablation randomized trial for extensive disease in prostate cancer. Clin Adv Hematol Oncol 4:588–590 22. Tombal B, Borre M, Rathenborg P et al (2014) Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study. Lancet Oncol 15:592–600
ORIGINAL ARTICLE
Significance of baseline bone markers on disease progression and survival in hormone‑sensitive prostate cancer with bone metastasis Masahiro Nozawa · Isao Hara · Hideyasu Matsuyama · Masayuki Iki · Kazuhiro Nagao · Tsukasa Nishioka · Takahiro Komura · Atsunobu Esa · Shigeya Uejima · Masaaki Imanishi · Yasunari Uekado · Takatoshi Ogawa · Hiroshi Kajikawa · Hirotsugu Uemura
Received: 30 July 2014 / Accepted: 23 October 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose This study evaluated the baseline patient characteristics associated with the time to biochemical progression and overall survival in patients who participated in a phase II trial on zoledronic acid combined with the initial androgen-deprivation therapy for treatment-naïve bonemetastatic prostate cancer. Methods Patients received zoledronic acid 4 mg intravenously every 4 weeks for up to 24 months, concomitantly started with bicalutamide 80 mg orally every day and goserelin acetate 10.8 mg subcutaneously every 12 weeks. Results A total of 53 Japanese patients were enrolled between July 2008 and April 2010, and 52 patients were evaluable. Median follow-up period was 41.6 months. Updated median time to biochemical progression was
25.9 months (95 % confidence interval 14.5–49.9). Higher serum bone-specific alkaline phosphatase was an independent risk factor for time to biochemical progression based on multivariate analysis (hazard ratio 6.51; 95 % confidence interval 2.71–15.62; P 249.4 ≤300 >300 ≤26.0 >26.0 ≤5.0 5.08.0 ≤50 50100
Multivariate (step-up procedure) 95 % CI
P value
Reference 0.52 Reference 1.39 Reference 1.58 Reference 2.59 Reference 1.89 Reference 1.91 Reference 2.98 Reference 1.76 Reference 2.16 Reference 6.51 Reference 0.91 2.76 Reference 3.05
(1.15–8.12)
0.025
6.82
(2.59–17.98)
300 ≤26.0 >26.0 ≤5.0 5.08.0 ≤100 >100
Reference 0.94 Reference 2.25 Reference 1.34 Reference 1.67 Reference 0.56 Reference 0.99 Reference 6.67 Reference 1.21 Reference 4.78 Reference 3.38 Reference 1.01 8.59 Reference 5.24
Multivariate (step-up procedure) 95 % CI
P value
(0.34–2.61)
0.910
(0.72–7.08)
0.165
(0.47–3.82)
0.584
(0.53–5.24)
0.383
(0.20–1.55)
0.268
(0.33–2.96)
0.983
(2.26–19.71)
0.001
(0.43–3.34)
0.721
(1.07–21.25)
0.040
(1.07–10.63)
0.037
(0.14–7.19) (1.89–39.07)
0.990 0.005
(1.77–15.47)
0.003
HR
95 % CI
P value
Reference 1.01 9.62
(0.14–7.18) (2.11–43.89)
0.991 0.003
ALP alkaline phosphatase, BAP bone-specific alkaline phosphatase, CI confidence interval, ECOG PS Eastern Cooperative Oncology Group performance status, EOD extent of bone disease, HR hazard ratio, ICTP C-terminal telopeptide of type I collagen, PSA prostate-specific antigen, uNTx urinary N-terminal cross-linked telopeptide of type I collagen
improved OS compared with placebo in metastatic CRPC [18]. Cabozantinib, a tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2, indicated improvement on bone scan in 68 % of patients with CRPC, including complete resolution in 12 % based on a phase II trial [19]. The efficacy of these new treatments against metastatic bone diseases should be theoretically promising not only for CRPC, but also for hormone-naïve PCa. There are some limitations to the current study, namely being that findings from the study are based on the data from a non-randomized single-arm phase II trial with a small number of subjects. In addition, the markers used are well known. Although no direct clinical impact can be derived because of the absence of a control arm, this study provides proof of principle that baseline bone markers may serve as predictors for biochemical progression and overall survival. We did not evaluate the association between the transition
of bone markers during treatment and clinical outcomes. In CRPC, the association between bone marker levels and clinical outcomes were stronger for on-study bone marker levels compared with baseline levels although the statistical heterogeneity in the strength of these correlations has not been reported [20]. We did not investigate the effect of treatments after disease progression with the initial ADT on OS. Docetaxel, abiraterone, enzalutamide, radium-223, and cabazitaxel can influence OS. The landscape for the treatment of hormone-naïve PCa has changed since the conception of the present study; docetaxel with ADT can improve overall survival compared with ADT alone [21], and abiraterone or enzalutamide may prove their value in this setting in the future (NCT01715285, NCT01957436) [22]. In conclusion, baseline bone markers may be useful as predictors for disease progression and survival in patients with bone metastases from treatment-naïve PCa who start treatment with ZA concomitant with ADT. Development of
13
World J Urol 1.0
p = 1.000
Probability
0.8
p = 0.005
0.6
p = 0.003 0.4
ICTP (ng/ml)
0.2
Median (95% CI) (months)
≤5.0 NA (NA-NA) >5.0, ≤8.0 NA (44.8-NA) >8.0 31.1 (19.0-NA)
0.0 0
500
1000
1500
(day)
Number at risk ICTP ≤5.0 18 ICTP >5.0, ≤8.0 17 ICTP >8.0 17
17 16 15
16 16 6
6 6 2
Fig. 2 Kaplan–Meier curves for overall survival stratified with baseline serum C-terminal telopeptide of type I collagen (ICTP) level
novel treatment strategies against metastatic bone diseases may improve the prognosis even in patients with hormonesensitive PCa. Acknowledgments The authors thank all patients and their families for participating in this study, all investigators and site staff for their contribution, and Marco De Velasco for reviewing the language. Conflict of interest The authors have no conflict of interest. Ethical standard The study was conducted according to the Declaration of Helsinki with approval from ethics committees at each institution. Written informed consent was obtained from all patients consistent with local requirements.
References 1. Coleman RE (2004) Bisphosphonates: clinical experience. Oncologist 9:14–27 2. Oefelein MG, Ricchiuti V, Conrad W, Resnick MI (2002) Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 168:1005–1007 3. Nørgaard M, Jensen AØ, Jacobsen JB, Cetin K, Fryzek JP, Sørensen HT (2010) Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol 184:162–167 4. Sathiakumar N, Delzell E, Morrisey MA et al (2011) Mortality following bone metastasis and skeletal-related events among men with prostate cancer: a population-based analysis of US
13
medicare beneficiaries, 1999–2006. Prostate Cancer Prostatic Dis 14:177–183 5. Saad F, Gleason DM, Murray R et al (2002) A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 94:1458–1468 6. Nozawa M, Inagaki T, Nagao K et al (2014) Phase II trial of zoledronic acid combined with androgen-deprivation therapy for treatment-naïve prostate cancer with bone metastasis. Int J Clin Oncol 19:693–701 7. Scher HI, Halabi S, Tannock I et al (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the prostate cancer clinical trials working group. J Clin Oncol 26:1148–1159 8. Maeda H, Koizumi M, Yoshimura K, Yamauchi T, Kawai T, Ogata E (1997) Correlation between bone metabolic markers and bone scan in prostatic cancer. J Urol 157:539–543 9. Aruga A, Koizumi M, Hotta R, Takahashi S, Ogata E (1997) Usefulness of bone metabolic markers in the diagnosis and follow-up of bone metastasis from lung cancer. Br J Cancer 76:760–764 10. Cook RJ, Coleman R, Brown J et al (2006) Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res 12:3361–3367 11. Smith MR, Cook RJ, Coleman R et al (2007) Predictors of skeletal complications in men with hormone-refractory metastatic prostate cancer. Urology 70:315–319 12. Lara PN Jr, Ely B, Quinn DI et al (2014) Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: results from SWOG 0421. J Natl Cancer Inst 106: dju013 13. Berruti A, Dogliotti L, Gorzegno G et al (1999) Differential patterns of bone turnover in relation to bone pain and disease extent in bone in cancer patients with skeletal metastases. Clin Chem 45:1240–1247 14. Hollier BG, Evans K, Mani SA (2009) The epithelial-to-mesenchymal transition and cancer stem cells: a coalition against cancer therapies. J Mammary Gland Biol Neoplasia 14:29–43 15. Lévesque JP, Helwani FM, Winkler IG (2010) The endosteal ‘osteoblastic’ niche and its role in hematopoietic stem cell homing and mobilization. Leukemia 24:1979–1992 16. Sun Y, Wang BE, Leong KG et al (2012) Androgen deprivation causes epithelial-mesenchymal transition in the prostate: implications for androgen-deprivation therapy. Cancer Res 72:527–536 17. Fizazi K, Carducci M, Smith M et al (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377:813–822 18. Parker C, Nilsson S, Heinrich D et al (2013) Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 369:213–223 19. Smith DC, Smith MR, Sweeney C et al (2013) Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 31:412–419 20. Brown JE, Cook RJ, Major P et al (2005) Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J Natl Cancer Inst 97:59–69 21. Sweeney CJ (2006) ECOG: CHAARTED–ChemoHormonal therapy versus androgen ablation randomized trial for extensive disease in prostate cancer. Clin Adv Hematol Oncol 4:588–590 22. Tombal B, Borre M, Rathenborg P et al (2014) Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study. Lancet Oncol 15:592–600
