To examine the effect of timely zoledronic acid (ZA) treatment on clinical outcomes and health care utilization in patients with bone-metastatic prostate cancer. Patients with prostate cancer and bone metastasis were identified in a Veterans Affairs database (01/2002–09/2009). Eligible patients had no documented skeletal-related events (SREs) before the index date (that is, the first bone metastasis diagnosis date). Patients who received early ZA treatment, defined as having a ZA infusion after the index date and before any recorded SREs, were matched 1:1 on propensity score to patients not treated with bisphosphonates (BPs). Risks of SREs, hospitalization and death during the 6-month post-index period were compared between matched cohorts using Kaplan–Meier analyses. Baseline characteristics were well balanced between the matched cohorts (n=73 per group). 6-month SRE-free survival and hospitalization-free survival were higher in patients receiving timely ZA than patients without BP treatment (91.7 versus 71.5%, P<0.01; 80.5 versus 66.3%, P=0.05, respectively). 6-month mortality risk was significantly lower in patients treated with ZA versus those without BP treatment (4.3 versus 13.8%, P=0.04). Timely ZA intervention in bone-metastatic prostate cancer patients was associated with significant reductions in 6-month risks of SREs, hospitalization and mortality, as compared with no BP treatment.
Prostate cancer is the most common malignancy in males in the United States, with almost 200 000 newly diagnosed cases in 2003.1 Bone metastasis frequently develops in patients with advanced prostate cancer and adds substantially to the disease-specific morbidity and mortality.2, 3 Bone lesions from prostate cancer are usually osteoblastic, but are often associated with bone resorption and osteolysis.4 The extent of bone metastases and associated skeletal complications is correlated with increasingly poorer prognosis,5, 6 and the incidence of bone metastases among prostate cancer is reported to be between 65 and 75%.7 Bone metastases are often symptomatic and can lead to debilitating bone pain that requires radiation therapy or surgery, pathological fractures and spinal cord compression.8 These skeletal-related events (SREs) contribute significantly to quality of life impairment and loss of functionality in patients with cancer.6, 9
First-line therapy for symptomatic metastatic prostate cancer typically consists of androgen deprivation therapy, with additional hormone manipulation or chemotherapy after disease progression.10 Androgen deprivation therapy is effective in inhibiting cancer growth but is rarely curative, because most patients will eventually develop hormone-refractory disease. Patients with hormone-refractory metastatic prostate cancer in particular are at a high risk of developing SREs.11 Consequently, bone-targeted therapy has become an important component of prostate cancer management in this patient population. Bisphosphonate (BP) therapy is an effective therapeutic option for reducing the risk of pathological fractures and other SREs in bone-metastatic prostate cancer.12
Zoledronic acid (ZA) is a potent BP with inhibitory effects on both osteoblastic and osteolytic metastasis in prostate cancer.13, 14, 15 Treatment guidelines recommend the administration of ZA 4 mg as an intravenous infusion every 3–4 weeks in hormone-refractory men with bone-metastatic prostate cancer. ZA is generally well tolerated, although monitoring of calcium levels and renal function (creatinine clearance >30 ml min−1) is recommended before administration of drug therapy. A large, randomized, placebo-controlled clinical trial of ZA in patients with hormone-refractory metastatic prostate cancer demonstrated significant clinical benefits, including delayed median time to the first SRE. 16, 17 Studies have also found statistically significant alleviation of bone pain in patients treated with ZA compared with placebo.17, 18
At present, the overall survival benefits of ZA in bone-metastatic prostate cancer are unclear. A previous study of ZA in metastatic prostate cancer did not detect significant differences in disease progression or performance status between ZA and placebo.16, 17 However, because a large proportion of patients enrolled in the trial had experienced skeletal complications before randomization,16 additional research is needed to examine the effect of timely ZA treatment, administered before the development of SREs, on subsequent SRE risk and survival outcomes in bone-metastatic prostate cancer patients. Clinical trials have shown evidence of anticancer activity with ZA in other solid tumors and hematological malignancies. In a trial of patients with early-stage breast cancer, ZA was associated with prolonged disease-free survival and decreased risk of breast cancer recurrence compared with standard care.19 A retrospective analysis of a phase III study suggested that ZA therapy may improve survival in a subgroup of lung cancer patients with high bone turnover when compared with placebo.20, 21 Another study showed better survival with ZA over clodronate in newly diagnosed multiple myeloma patients.22
The present study retrospectively examined the outcomes of ZA treatment in a population of US veterans with bone-metastatic prostate cancer. The research objective was to compare the risks of SREs, hospitalization and mortality in patients who received timely administration of ZA versus those who did not receive BP therapy.
A retrospective database analysis was performed using electronic medical record data from South Central Veteran's Affairs Health Care Network (VISN 16) data warehouse. The VISN 16 data warehouse is an integrated, de-identified, individual-level database that covers a geographic region of ∼170 000 square miles, and includes records for more than 445 000 veterans located in Arkansas, Louisiana, Mississippi, Oklahoma, and parts of Alabama, Florida, Missouri and Texas. The health care network represents 10 medical centers and 40 community-based outpatient clinics. The database contains demographic data, inpatient and outpatient records, pharmacy prescriptions, lab results, vital-sign data (height, body weight) and mortality information (date of death) for each patient treated within the network. A tumor registry, which captures data on cancer stage, therapies and disease recurrence for cancer patients in the network, is also available in the database. The data warehouse is updated monthly and maintained by the VISN 16 Information Technology Development Group. Data covering the period from January 2002 to September 2009 were used in order to capture outcomes following the FDA approval of ZA for patients with metastatic prostate cancer refractory to at least one hormonal therapy.
Patients were included in the study if they had at least one diagnosis for prostate cancer (International Classification of Disease-9-Clinical Modification (ICD-9-CM): 185.xx) from 1 January, 2002 to September 30, 2009. Prostate cancer diagnoses were confirmed by the inclusion of the patients in the VISN 16 cancer registry. Included patients were also required to have at least one diagnosis of secondary malignant neoplasm of bone (ICD-9-CM: 198.5) and/or confirmed in the staging file. The index date for each patient was defined as the date of the first diagnosis of bone metastasis.
Additional selection criteria were applied to identify the treated cohort and control cohort for the study. The treated cohort included patients who received timely treatment with ZA, while the control cohort consisted of patients without any recorded BP use in the database. Treatment with ZA was considered timely if the therapy was administered after the first diagnosis of bone metastasis and before the first SRE. This definition of timely treatment was used in order to select patients who received ZA for prevention of SREs after developing bone metastasis. In both the treated and control cohorts, patients were required to have no documented SREs or hypercalcemia (ICD-9-CM: 275.42) before the first diagnosis of bone metastasis. SREs included bone fracture (ICD-9-CM: 733.1x, 733.81–733.82, 805.xx–806.xx, 800.xx–804.xx, 807.0x–807.3x, 808.xx–828.xx, 830.xx–839.xx and 850.xx–854.xx), spinal cord compression (ICD-9-CM: 336.9x), surgery to bone or radiation therapy to bone. Bone surgeries were identified in the database based on a comprehensive list of ICD-9-CM procedure and Current Procedural Terminology codes that has been used in previous research (Krupski et al.23). To identify radiation therapy to relieve bone pain, Current Procedural Terminology codes for external beam radiotherapy (77401–77404, 77406–77409, 77411–77414, 77416, 77418 and 77427) and Healthcare Common Procedure Coding System codes for radiopharmaceuticals including Samarium-153 (A9605), Strontium-89 (A9600) and P-32 (A9563) were applied.
To address potential selection bias and control for between-group differences in patient characteristics and disease severity at baseline, propensity score matching method was used to generate two cohorts of patients who met the inclusion criteria and had an overall similarity in their baseline characteristics. Because of the smaller number of patients who were timely treated with ZA, the treated cohort and control cohort were matched at a ratio of 1:1. Using logistic regression, the propensity score (that is, the likelihood of receiving timely ZA treatment versus no BP therapy) was estimated for each patient. One control patient with the closest propensity scores was matched to each treated patient. The characteristics of the patients that were considered in the propensity score calculation included age, ethnicity, geographical region, presence of related comorbidities and Charlson comorbidity index during the 6-month pre-index period, previous use of steroids and history of cancer therapies (that is, previous chemotherapy, radiation therapy, surgeries and androgen deprivation therapy). In addition, patients were exactly matched on previous renal impairment and bone loss status. Renal impairment was identified by renal failure (ICD-9-CM: 584.xx, 586.xx), chronic kidney disorders stage III and above (ICD-9-CM: 585.3x, 585.4x, 585.5x, 585.6x and 585.9x) or disorders resulting from impaired renal function (ICD-9-CM: 588.xx). Bone loss was defined to be osteopenia (ICD-9-CM: 733.90) or osteoporosis (ICD-9-CM: 733.0x), conditions characterized by low bone mass and loss of bone tissue that can lead to increased risk for fractures bones.
The study period was designated a priori as the 6 months following the diagnosis of bone metastasis in consideration of the short survival of prostate cancer patients at the stage of bone metastasis and natural-cause death; the veterans in the matched sample had an average age of ∼70 years. The flow chart in Figure 1 summarizes the sample selection process and corresponding sample sizes.
Baseline characteristics, including demographics, comorbidity profiles, disease history and previous treatments during the 6-month pre-index baseline period, were summarized and compared between the matched study cohorts. Statistical comparisons were conducted using χ2-tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.
Time to the first SRE, time to the first hospitalization and overall survival rates were evaluated during the first 6 months after the diagnosis of bone metastasis and compared between the cohorts using survival analysis. The occurrence of SREs was determined based on diagnosis codes associated with inpatient and outpatient medical records of the patients. Hospitalization events were identified using inpatient admission records. Dates of death reported in the patient enrollment files were used to evaluate survival over 6 months. Time to event and overall survival within the 6-month study period were analyzed using the Kaplan–Meier method and log-rank tests. In the time to event analyses, patients were observed from their index date to the first event, and were censored at data availability or the end of the 6-month post-index period, whichever occurred earliest. Similarly, the analysis of overall survival followed patients to their date of death, with censoring at the end of eligibility or the end of the 6-month study period.
Before propensity score matching, a total of 585 patients in the database met the study inclusion criteria. Among these patients, 73 patients received timely ZA therapy, while the remaining 512 patients did not receive any BP treatment. Compared with patients without any BP therapy, those who received timely ZA treatment were older on average (69.2 versus 66.5 years, P=0.02), and were significantly more likely to have had a previous bone loss diagnosis (12.3 versus 2.2%, P<0.01) (Table 1). A substantially higher proportion of patients in the ZA-treated cohort had received previous androgen deprivation therapy than in the control cohort (49.3 versus 11.7%, P<0.01). In both groups, diabetes, hypertension, hyperlipidemia and osteoarthritis were the common diagnoses during the baseline period.
The final study sample consisted of 73 pairs of 1:1 propensity score-matched patients from the treated and control cohorts. No significant differences were observed between the matched cohorts in terms of baseline demographics, comorbidity profiles or cancer treatment history.
In the Kaplan–Meier analysis, prostate cancer patients who received timely treatment with ZA were significantly less likely to experience an SRE during the study period than those who did not receive BP therapy (Figure 2). Cumulative SRE-free survival for patients in the ZA-treated and control cohorts were 94.5 versus 77.8% at 3 months, and 91.7 versus 71.5% at 6 months (P<0.01).
Compared with patients without BP therapy, patients with timely ZA treatment had a lower likelihood of hospitalization over 6 months (Figure 3). Hospitalization-free survival at 6 months was 80.5% within the treated cohort compared with 66.3% in the control cohort (P=0.05).
Timely treatment with ZA was also associated with better overall survival relative to no BP treatment (Figure 4). The overall survival at 6 months among ZA-treated patients was 95.7%, significantly higher than the survival of 86.2% among patients without BP therapy (P=0.04).
In this retrospective analysis of electronic medical records, timely treatment with ZA was associated with lower risks of SREs, hospitalization and mortality over 6 months when compared with no BP treatment in prostate cancer patients with bone metastasis. Several randomized placebo-controlled clinical trials have demonstrated reductions in the incidence of SREs and delayed median time to the occurrence of SREs with ZA.16, 17 Results from the analysis of SRE outcomes confirm findings from other metastatic prostate cancer studies, and confirm the benefits of ZA in reducing skeletal morbidity.
Consistent with the evidence of ZA anticancer activities from recent breast cancer studies,19, 24, 25, 26 we found evidence of prolonged overall survival with ZA among patients with prostate cancer. While earlier studies of ZA in prostate cancer did not show significant overall survival benefit with this therapy, the present study found that timely ZA treatment significantly reduced mortality risk during the first 6 months after diagnosis of bone metastasis. The differences in the findings across the prostate cancer studies may be a result of study sample selection. Notably, in a clinical trial among hormone-refractory metastatic prostate cancer patients, the average enrolled patient had their first bone metastases 26 months before randomization, and 33% of patients had previously experienced an SRE.16 In contrast, the present analyses followed patients from the time of their first recorded bone metastasis, and only included patients without previous SREs. In order to further verify the ZA's survival benefit in prostate cancer, future research with a larger sample is warranted to examine whether earlier intervention with ZA has more potential to improve overall survival in prostate cancer patients.
This study is subject to several limitations, including the general limitations of observational and retrospective analyses. First, limited clinical data were available in the electronic medical record database used for this study. The database does not provide complete information on PSA measurements, performance status, bone scan or bone mineral density data, or rationale for treatment decisions. Although the analysis controlled for a variety of baseline factors using propensity score matching techniques, the clinical reasons for receiving timely ZA treatment versus not receiving any BP therapy could not be recorded and adjusted for in the outcomes comparison. There may be residual selection bias from other baseline factors not observable in medical records of patients. For example, some patients may be excluded from BP therapy because of active dental problems. Also, patients with hormonally sensitive disease may tend to be managed in office settings by urologists, who may have limited facilities or trained staff to administer BP infusions. All patients were enrolled in the US Veterans Affairs health system, which may reduce the representativeness of the study sample. Veterans may have unique preferences and psychosocial situations that influence their medical treatment. Some may decline therapy because of preference or concerns regarding the convenience of monthly BP infusions. The VISN 16 data warehouse also includes more rural areas and small communities. Finally, because the sample size available for this study was relatively small, further research with a larger patient sample is warranted to further confirm the study findings.
This retrospective analysis of a Veteran Affairs health system database demonstrated that bone-metastatic prostate cancer patients who received timely treatment with ZA had lower 6-month risks of SREs, mortality and hospitalization compared with those without any BP treatment.
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The funding for this study was provided by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. We wish to thank the Veterans Integrated Service Networks (VISN) 16 data warehouse for the de-identified data set. The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States Government. The authors thank Arielle Bensimon for editing the manuscript.
NV Velde, L Shi, and J Liu are affiliated with Tulane University and Southeast Louisiana Veterans Health Care System and do not have financial interest associated with this publication. Similarly, EQ Wu, M Lu, AP Yu, H Sharma and CPS Fan are employees of Analysis Group, Inc. and do not have financial interest associated with this publication. A Guo is an employee of Novartis Pharmaceuticals and may hold stocks of the company.
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Risk of skeletal related events among elderly prostate cancer patients by site of metastasis at diagnosis
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