Clinical indicators for predicting prognosis after radium-223 administration in castration-resistant prostate cancer with bone metastases

Abstract

Background

Radium-223 (Ra-223) is a targeted alpha therapy that has been shown to prolong overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. However, prognosis after Ra-223 administration varies among patients. The aim of the present study was to assess risk factors associated with the poor prognosis of patients treated with Ra-223.

Methods

We retrospectively reviewed patients’ records of treatment with Ra-223 between October 2016 and December 2019. All patients had mCRPC, bone metastasis, and no known visceral metastases, and received up to six cycles of Ra-223 (55 kBq/kg). Prognostic factors for OS were analyzed by Cox proportional hazards model and log-rank test.

Results

We identified 42 patients who received at least one cycle of Ra-223 (median six cycles, range 1–6). Approximately two-thirds of patients had received at least two lines of therapy for mCRPC. The median age was 74 years, and the median follow-up duration was 13.6 months. The median OS time was 16.6 months. On multivariate analysis, PSA doubling time (PSADT) (0–3 months) at baseline, number of bone metastases (≥ 20), and treatment line of Ra-223 (4th–5th line) remained significantly correlated with the poor OS (HR 4.354, P = 0.003; HR 2.855, P = 0.020; and HR 4.871, P = 0.001, respectively).

Conclusions

Our study demonstrated that a shorter PSADT, a heavier volume of bone metastases, and a later treatment line before Ra-223 are poor prognostic factors for mCRPC patients. These newly discovered risk factors may help select patients who potentially have long-term OS after Ra-223 treatment.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2

Abbreviations

AE:

Adverse event

ALP:

Alkaline phosphatase

HR:

Hazard ratio

mCRPC:

Metastatic castration-resistant prostate cancer

LDH:

Lactate dehydrogenase

OS:

Overall survival

OR:

Odds ratio

PS:

Performance status

PSADT:

PSA doubling time

Ra-223:

Radium-223

References

  1. 1.

    James ND, Spears MR, Clarke NW et al (2015) Survival with newly diagnosed metastatic prostate cancer in the “Docetaxel Era”: data from 917 patients in the control arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). Eur Urol 67:1028–1038

    PubMed  Article  Google Scholar 

  2. 2.

    Tannock IF, de Wit R, Berry WR et al (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502–1512

    CAS  Article  Google Scholar 

  3. 3.

    Kantoff PW, Higano CS, Shore ND et al (2010) Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411–422

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    de Bono JS, Oudard S, Ozguroglu M et al (2010) Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial. Lancet 376:1147–1154

    PubMed  Article  Google Scholar 

  5. 5.

    de Bono JS, Logothetis CJ, Molina A et al (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364:1995–2005

    PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Scher HI, Fizazi K, Saad F et al (2012) Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367:1187–1197

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    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

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Sartor O, Coleman R, Nilsson S et al (2014) Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 15:738–746

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Nilsson S, Cislo P, Sartor O et al (2016) Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol 27:868–874

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Vogelzang NJ, Coleman RE, Michalski JM et al (2017) Hematologic safety of radium-223 dichloride: baseline prognostic factors associated with myelosuppression in the ALSYMPCA trial. Clin Genitourin Cancer 15:42–52.e8

    PubMed  Article  Google Scholar 

  11. 11.

    Saad F, Carles J, Gillessen S et al (2016) Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial. Lancet Oncol 17:1306–1316

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Sartor O, Coleman RE, Nilsson S et al (2017) An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the phase 3 ALSYMPCA trial with radium-223. Ann Oncol 28:1090–1097

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    McKay RR, Jacobus S, Fiorillo M et al (2017) Radium-223 use in clinical practice and variables associated with completion of therapy. Clin Genitourin Cancer 15:e289–e298

    PubMed  Article  Google Scholar 

  14. 14.

    Naito M, Ukai R, Hashimoto K (2019) Bone scan index can be a useful biomarker of survival outcomes in patients with metastatic castration-resistant prostate cancer treated with radium-223. Cancer Rep 2:e1203

    Google Scholar 

  15. 15.

    Epstein JI, Egevad L, Amin MB et al (2016) The 2014 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma: definition of grading patterns and proposal for a new grading system. Am J Surg Pathol 40:244–252

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Memorial Sloan-Kettering Cancer Center cancer information: prostate cancer nomogram. https://www.mskcc.org/nomograms/prostate/psa_doubling_time. Accessed 1 May 2020

  17. 17.

    The Prostate Cancer Guidelines; European Association of Urology in 2020. https://uroweb.org/guideline/prostate-cancer/. Accessed 1 May 2020

  18. 18.

    NCCN Guidelines Version 1. 2020 Prostate Cancer. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed 1 May 2020

  19. 19.

    Saad F, Gillessen S, Heinrich D et al (2019) Disease characteristics and completion of treatment in patients with metastatic castration-resistant prostate cancer treated with radium-223 in an international early access program. Clin Genitourin Cancer 17:348–355.e5

    PubMed  Article  Google Scholar 

  20. 20.

    Antonarakis ES, Chen Y, Elsamanoudi SI et al (2011) Long-term overall survival and metastasis-free survival for men with prostate-specific antigen-recurrent prostate cancer after prostatectomy: analysis of the Center for Prostate Disease Research National Database. BJU Int 108:378–385

    PubMed  Article  Google Scholar 

  21. 21.

    Oudard S, Banu E, Scotte F et al (2007) Prostate-specific antigen doubling time before onset of chemotherapy as a predictor of survival for hormone-refractory prostate cancer patients. Ann Oncol 18:1828–1833

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Stewart AJ, Scher HI, Chen MH et al (2005) Prostate-specific antigen nadir and cancer-specific mortality following hormonal therapy for prostate-specific antigen failure. J Clin Oncol 23:6556–6560

    PubMed  Article  Google Scholar 

  23. 23.

    Fosbøl MØ, Petersen PM, Kjaer A et al (2018) 223 Ra therapy of advanced metastatic castration-resistant prostate cancer: quantitative assessment of skeletal tumor burden for prognostication of clinical outcome and hematologic toxicity. J Nucl Med 59:596–602

    PubMed  Article  Google Scholar 

  24. 24.

    Vidal M, Delgado A, Martinez C et al (2020) Overall survival prediction in metastatic castration-resistant prostate cancer treated with radium-223. Int Braz J Urol 46:599–611

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Parker CC, Coleman RE, Sartor O et al (2018) Three-year safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases from phase 3 randomized alpharadin in symptomatic prostate cancer trial. Eur Urol 73:427–435

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

The authors wish to thank the patients and their families for participating in this study, as well as the staff for supporting the study. We also thank H. Nikki March, PhD, from Edanz Group (https://www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

None.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Kazuo Nishimura.

Ethics declarations

Conflict of interest

KN received speaker honoraria from Astellas, Novartis and Bayer; research funding from Bayer outside the submitted work. Remaining authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yamamoto, Y., Okuda, Y., Kanaki, T. et al. Clinical indicators for predicting prognosis after radium-223 administration in castration-resistant prostate cancer with bone metastases. Int J Clin Oncol 26, 192–198 (2021). https://doi.org/10.1007/s10147-020-01776-w

Download citation

Keywords

  • Castration-resistant prostate cancer
  • Number of bone metastases
  • Overall survival
  • PSA doubling time
  • Radium-223