Zoledronic acid combined with androgen-deprivation therapy may prolong time to castration-resistant prostate cancer in hormone-naïve metastatic prostate cancer patients – A propensity scoring approach

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Abstract

Objective

To clarify the oncological benefit of zoledronic acid for hormone-naïve metastatic prostate cancer, patient outcome of androgen deprivation therapy with zoledronic acid (ADT + Z) and androgen deprivation therapy alone (ADT) was compared.

Methods

Fifty-two patients with pathologically confirmed metastatic prostate cancer were prospectively enrolled and treated with combined androgen blockade (goserelin and bicalutamide) with zoledronic acid (4 mg every 4 weeks for 24 months). A propensity score-match with logistic regression analysis was applied to select 50 pair-matched cohorts (both from ADT + Z and from historical control cohorts who had undergone ADT alone), and patient outcomes were compared.

Results

Patients with ADT + Z had significantly longer time to progression (TTP) than those with ADT (median TTP; 24.2 vs. 14.0 months, p = 0.0092), while no significant difference of overall survival between two groups ( p = 0.1502). Multivariate analysis for biochemical recurrence revealed treatment with ADT was the sole independent prognostic factor (HR: 1.724, 95% CI: 1.06–2.86, p = 0.0297).

Conclusion

Combination of zoledronic acid with ADT may prolong time to castration resistant prostate cancer.

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Most cited references 12

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The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators.

S Broste, Frank E. Harrell, W Knaus … (1996)

To examine the association between the use of right heart catheterization (RHC) during the first 24 hours of care in the intensive care unit (ICU) and subsequent survival, length of stay, intensity of care, and cost of care. Prospective cohort study. Five US teaching hospitals between 1989 and 1994. A total of 5735 critically ill adult patients receiving care in an ICU for 1 of 9 prespecified disease categories. Survival time, cost of care, intensity of care, and length of stay in the ICU and hospital, determined from the clinical record and from the National Death Index. A propensity score for RHC was constructed using multivariable logistic regression. Case-matching and multivariable regression modeling techniques were used to estimate the association of RHC with specific outcomes after adjusting for treatment selection using the propensity score. Sensitivity analysis was used to estimate the potential effect of an unidentified or missing covariate on the results. By case-matching analysis, patients with RHC had an increased 30-day mortality (odds ratio, 1.24; 95% confidence interval, 1.03-1.49). The mean cost (25th, 50th, 75th percentiles) per hospital stay was $49 300 ($17 000, $30 500, $56 600) with RHC and $35 700 ($11 300, $20 600, $39 200) without RHC. Mean length of stay in the ICU was 14.8 (5, 9, 17) days with RHC and 13.0 (4, 7, 14) days without RHC. These findings were all confirmed by multivariable modeling techniques. Subgroup analysis did not reveal any patient group or site for which RHC was associated with improved outcomes. Patients with higher baseline probability of surviving 2 months had the highest relative risk of death following RHC. Sensitivity analysis suggested that a missing covariate would have to increase the risk of death 6-fold and the risk of RHC 6-fold for a true beneficial effect of RHC to be misrepresented as harmful. In this observational study of critically ill patients, after adjustment for treatment selection bias, RHC was associated with increased mortality and increased utilization of resources. The cause of this apparent lack of benefit is unclear. The results of this analysis should be confirmed in other observational studies. These findings justify reconsideration of a randomized controlled trial of RHC and may guide patient selection for such a study.

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Exploring the anti-tumour activity of bisphosphonates in early breast cancer.

M.C. Winter, I Holen, R.E. Coleman (2008)

Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption and are firmly established in the management of breast cancer patients with metastatic skeletal disease. There are extensive data that bisphosphonates, particularly nitrogen-containing bisphosphonates such as zoledronic acid, exhibit anti-tumour activity potentially via both indirect and direct mechanisms in vitro. In vivo studies using animal models of breast cancer induced bone disease have shown that bisphosphonates exert anti-tumour effects via inhibiting osteolysis and reducing skeletal tumour burden. Furthermore, pre-clinical studies have demonstrated synergistic anti-tumour effects between chemotherapy agents commonly used in breast cancer treatment and nitrogen-containing bisphosphonates. This, coupled with emerging evidence from pre-clinical in vivo studies suggesting that bisphosphonates may have additional anti-tumour activity outside of the bone microenvironment, could be of significant importance in the clinical management of breast cancer. The evidence in favour of an anti-tumour effect of bisphosphonates in the clinical setting is inconclusive however, with conflicting evidence from several trials. This review focuses on the anti-tumour activity of bisphosphonates in breast cancer, with particular focus on zoledronic acid. The pre-clinical evidence for anti-tumour activity will be reviewed, followed by the synergistic effects with anti-cancer agents. Finally, the clinical relevance and strategies for the evaluation of anti-tumour activity in breast cancer will be discussed. We are currently exploring the potential synergistic anti-tumour effects of the sequential treatment of neoadjuvant chemotherapy followed by zoledronic acid in a randomised phase II study evaluating biological endpoints including apoptosis, proliferation and angiogenesis in patients with breast cancer.

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Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients.

Daniele Santini, Bruno Vincenzi, Sara Galluzzo … (2007)

On the basis of stimulating data on animals reporting that weekly regimens of zoledronic acid (ZA) were effective in reducing skeletal tumor burden, we designed a study on humans to investigate the potential antiangiogenic role of a weekly low-dose therapy with ZA in patients with malignancies. Twenty-six consecutive patients with advanced solid cancer and bone metastases received 1 mg of ZA every week for four times (days 1, 7, 14, and 21) followed by 4 mg of ZA with a standard 28-day schedule repeated thrice (days 28, 56, and 84). Patients were prospectively evaluated for circulating levels of vascular endothelial growth factor (VEGF) just before the beginning of drug infusion (0) and again at 7, 14, 21, 28, 56, and 84 days after the first ZA infusion. The median VEGF basal value showed an early statistically significant (P = 0.038) decrease 7 days after the first 1-mg infusion of ZA. This effect on VEGF-circulating levels persisted also after the following 1-mg infusions at 14 (P = 0.002), 21 (P = 0.001), and 28 days (P = 0.008). Interestingly, the decrease of VEGF-circulating levels persisted also at each programmed time point during the second phase of the study (ZA 4 mg every 4 weeks). No significant differences were recorded in platelet levels, WBC count, or hemoglobin concentration before and after each ZA infusion. In the present study, we report that a repeated low-dose therapy with ZA is able to induce an early significant and long-lasting decrease of VEGF levels in cancer patients.

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Author and article information

Contributors

Hideyasu Matsuyama

Journal

Journal ID (nlm-ta): Asian J Urol

Journal ID (iso-abbrev): Asian J Urol

Title: Asian Journal of Urology

Publisher: Second Military Medical University

ISSN (Print): 2214-3882

ISSN (Electronic): 2214-3890

Publication date PMC-release: 31 October 2015

Publication date (Print): January 2016

Publication date (Electronic): 31 October 2015

Volume: 3

Issue: 1

Pages: 33-38

Affiliations

[a ]Department of Urology, Graduate School of Medicine, Yamaguchi University, Japan

[b ]Department of Urology, Kinki University Faculty of Medicine, Japan

[c ]Department of Urology, Wakayama Medical University School of Medicine, Japan

[d ]Department of Urology, Sakai Hospital, Kinki University Faculty of Medicine, Japan

[e ]Department of Urology, Naga Hospital, Japan

[f ]Department of Urology, NTT Osaka Hospital, Japan

[g ]Department of Urology, National Hospital Organization Osaka Minami Medical Center, Japan

[h ]Department of Urology, Nara Hospital Kinki University Faculty of Medicine, Japan

[i ]Department of Urology, Tondabayashi Hospital, Japan

[j ]Department of Urology, Wakayama Rosai Hospital, Japan

[k ]Department of Urology, Kainan Municipal Hospital, Japan

[l ]Department of Urology, Izumiotsu Municipal Hospital, Japan

Author notes

[∗ ]Corresponding author. hidde@ 123456yamaguchi-u.ac.jp

Article

Publisher ID: S2214-3882(15)00114-9

DOI: 10.1016/j.ajur.2015.10.003

PMC ID: 5730815

SO-VID: d09f7ce5-84e1-4fbd-98a8-f1ebee028c21

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 7 April 2015

Date revision received : 30 July 2015

Date accepted : 12 October 2015

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Zoledronic acid combined with androgen-deprivation therapy may prolong time to castration-resistant prostate cancer in hormone-naïve metastatic prostate cancer patients – A propensity scoring approach

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Abstract

Objective

Methods

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Conclusion

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Cancer Metabolism

Most cited references 12

The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators.

Exploring the anti-tumour activity of bisphosphonates in early breast cancer.

Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients.

Author and article information

Contributors

Journal

Affiliations

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Cited by 1

Most referenced authors 333