Abstract
Background:
For patients with bone metastases, skeletal-related events including fracture are common, can cause considerable morbidity, and may reduce overall survival (OS). This retrospective analysis assessed the effect of Zometa (zoledronic acid, ZOL), an intravenous bisphosphonate (IV-BP), on fracture risk and OS in patients with bone metastases from lung cancer (LC). (Zometa is a registered trademark of Novartis Pharmaceuticals Corporation, USA.)
Methods:
A claims-based analysis using commercial and Medicare Advantage data from >45 US managed-care plans was used to evaluate the association between fracture risk and treatment persistency (31–90, 91–180, 181–365, and ≥366 days) and follow-up duration in LC patients diagnosed with bone metastases between 01/01/2001 and 12/31/2006 and treated with ZOL or without (no IV-BP). Persistency was defined as the absence of a >45-day gap between ZOL treatments. Analysis of variance tests were used to compare follow-up duration, a proxy for OS, between ZOL persistency groups. The effect of time to treatment with ZOL was also assessed.
Results:
In 9874 LC patients with bone metastases (n = 1090 ZOL; n = 8784 no IV-BP) the unadjusted relative fracture risk was reduced by 40% with ZOL vs no IV-BP; fracture risk decreased consistently with increasing duration of ZOL treatment. Even short-term (31–90 days) ZOL significantly reduced fracture risk (47%) vs no IV-BP (p = 0.005) with adjustment for differences in demographic and clinical characteristics. Delaying ZOL until after bone metastases were diagnosed significantly increased fracture risk (p = 0.0017). For a sub-set of patients included in a survival analysis (n = 550 ZOL; n = 4512 no IV-BP), mortality was significantly lower (mean, 38.6 vs 46.8 deaths/100 person-years; p = 0.038) in those treated with ZOL vs no IV-BP.
Limitations:
Interpretation of this claims-based analysis must be tempered by the inherent limitations of observational data, such as limited clinical information and the ability to control for prognostic factors.
Conclusions:
This retrospective analysis demonstrates that LC patients with bone metastases receiving ZOL had significantly reduced risk of fracture (p = 0.005) and death (p < 0.038) vs patients receiving no IV-BP. Longer ZOL persistency consistently yielded better outcomes, with ≥12 months’ treatment producing the greatest benefit.
Keywords::
Introduction
Bone is the most common site of metastatic disease for patients with solid tumors. Bone metastases develop in ∼30–40% of patients with advanced lung cancer and may result in potentially debilitating pain and an increased risk of skeletal-related events (SREs: pathologic fracture, spinal cord compression, severe bone pain, the need for palliative radiotherapy or surgery to the bone, and hypercalcemia of malignancy [HCM])Citation1–3. With new advances in chemotherapeutic strategies, the survival of patients with advanced lung cancer has improved, thus allowing the effects of tumor on bone to manifest in multiple debilitating and potentially life-limiting SREsCitation4–6.
Skeletal complications can be associated with substantial morbidity, reduced quality-of-life, and, in some patient sub-sets, reduced survivalCitation7,Citation8. In a retrospective review of patients with stage III/IV non-small cell lung cancer (NSCLC), median survival was up to 12 months for patients who did not develop SREs, but only ∼6 months for those who developed SREsCitation4.
Studies suggest that, in the absence of bone-targeted therapy, greater than half of patients with bone metastases from lung cancer experience at least one SRE within their lifetime, typically within 2 months of being diagnosed with the lesionsCitation9. Moreover, patients who have already experienced an SRE have an increased risk of experiencing subsequent SREs, and ∼25% of patients experience at least two SREs throughout the course of their diseaseCitation9,Citation10. A retrospective exploratory analysis of a phase 3 trial in patients (n = 503) with bone metastases from lung cancer or other solid tumors demonstrated that patients with a history of SREs before study entry (n = 347) have a 40% increased risk of experiencing an on-study SRE compared with patients with no prior SRE (p = 0.036)Citation10.
In addition to negative effects on patient outcomes, SREs are associated with increased healthcare costsCitation9,Citation11–13. For example, in a retrospective study using data derived from employer-paid commercial or Medicare supplemental insurance plans from 2000–2004, the mean monthly incremental costs were $24,946 (€17243) higher for patients with metastatic bone disease from lung cancer compared with patients with lung cancer without metastatic bone disease (p < 0.001)Citation14. Similarly, economic analyses in Europe revealed SRE-related treatment costs ranging between ∼€4400 ($6368) and €7200 ($10,420) beyond the standard costs of anti-cancer therapies for patients with bone metastases from lung cancerCitation12. Therefore, bone metastases from lung cancer continue to present a substantial clinical and health-economic problem.
Because of the potential negative disease-related and cost outcomes associated with metastatic bone disease in patients with lung cancer, bone-targeted therapies are an especially important component of care. Intravenous (IV) bisphosphonates (BP) inhibit osteoclast-mediated bone resorption and can reduce the risk of SREs associated with bone metastases. Zometa (zoledronic acid, ZOL), a new-generation IV-BP, has been shown to effectively delay the onset and reduce the incidence of SREs in patients with bone metastases from multiple tumor types including breast, prostate, lung, and other solid tumors, and is the only bone-targeted agent to have received international regulatory approval for use in these clinical settingsCitation15–20. (Zometa is a registered trademark of Novartis Pharmaceuticals Corporation, USA.) In a phase 3, multi-center, randomized, placebo-controlled trial in patients with bone metastases from a broad range of solid tumors including NSCLC, ZOL (4 mg via 15-min IV infusion every 3 weeks for up to 21 months) significantly reduced the percentage of patients who experienced ≥1 SRE (p = 0.039), significantly delayed the median time to first on-study SRE by ≥2 months (p = 0.009), and significantly reduced the overall risk of SREs by 31%, as assessed by multiple event analysis (hazard ratio [HR] = 0.693; p = 0.003), compared with placeboCitation15. In a retrospective exploratory analysis of the phase 3 trial described above, among patients with an SRE before study entry who were treated with 4 mg ZOL, an absolute 10% fewer experienced an on-study SRE compared with placebo (p = 0.030) and had a median time to first on-study SRE that was significantly prolonged by 109 days (p = 0.011)Citation10. Moreover, in patients at increased risk of SREs, ZOL continued to protect against SREs (risk reduction of 35% vs placebo) despite progression of the underlying diseaseCitation21.
Guidance regarding initiation and duration of ZOL in patients with bone metastases from lung cancer is limited. However, data suggest that continuous, long-term treatment may result in improved outcomes. A retrospective study evaluating persistency with ZOL (i.e., continuous duration of regular treatment as prescribed) demonstrated that longer persistency with therapy is associated with a reduced incidence of SREs and prolonged time to first SRECitation22. The time to first SRE was ∼8 months for patients persisting with ZOL for >6 months vs ∼2.5 months for patients persisting with treatment ≤3 monthsCitation22. These observations suggest that early and sustained treatment with ZOL might improve overall clinical outcomes in patients with lung cancer and bone metastases. In this retrospective claims-based study, the effects of treatment with ZOL on the risk of fracture and on overall survival in patients with bone metastases from lung cancer were evaluated. The effects of time of initiation and duration of ZOL therapy were also assessed.
Methods
Data sources
This was a retrospective claims-based analysis using medical, pharmacy, and patient enrollment data collected between July 1, 2000, and December 31, 2007. Data were collected from two large, nationally representative care-plan databases in the US with commercial and Medicare Advantage patient enrollment and claims data: a database affiliated with OptumInsight (formerly Innovus) and the OptumInsight/IHCIS Impact National Managed Care Database (IMPACT). To create the IMPACT database, OptumInsight compiles claims data submitted by healthcare providers and pharmacies to ∼45 health plans for reimbursement. Medical claims included multiple diagnosis codes recorded with the International Classification of Diseases, Ninth Revision (ICD-9-CM) diagnosis codes; procedures recorded with ICD-9-CM procedure codes, Current Procedural Terminology (CPT), or Health Care Financing Agency (HCFA) Common Procedure Coding System (HCPCS) codes; site of service codes; provider specialty codes; revenue codes (for facilities); and paid amounts. Claims for ambulatory services submitted by individual providers used the HCFA-1500 format, and claims for facility services submitted by institutions used the UB-82 or UB-92 formats. Typically, facility claims do not include any drugs administered in the hospital or purchased over the counter. Approximately 6 months following the delivery of services is required for availability of complete medical data. Claims for pharmacy services are typically submitted electronically by the pharmacy at the time prescriptions are filled. Pharmacy claims data include drug name, dosage form, drug strength, fill date, days of supply, and de-identified patient and prescriber codes. Pharmacy claims are typically added to the research database within 6 weeks of dispensing.
Patient selection
This analysis included commercial and Medicare Advantage health plan members with ≥1 medical claim for lung cancer (ICD-9-CM codes 162.3 to 162.9) from January 1, 2001, through December 31, 2006 (). Additionally, to be included in the analysis members were required to have evidence of bone metastasis and a claim for monthly ZOL during the study period. Bone metastases were identified based on the presence of ≥1 claim indicating bone metastasis (ICD-9-CM diagnosis code 198.5x) or ≥1 claim for lung cancer in any position and a diagnosis code of 170.x (malignant neoplasm of bone and articular cartilage) in a secondary position. The date of the first claim for bone metastasis or monthly ZOL was set as the index date. To be included in the analysis, members were also required to be ≥18 years of age as of the index date and to have continuous health plan enrollment for ≥6 months before the index date.
Figure 1. Patient disposition diagram. IV, intravenous; met, metastasis; PAM, pamidronate; ZOL, zoledronic acid.
Members were excluded from the analysis if they had evidence of bone metastases or monthly ZOL in the 6 months before the index date. Patients who initiated ZOL >30 days after a bone metastasis diagnosis were also excluded to enable comparison of similar patient cohorts (i.e., similar opportunity for treatment exposure). A claim for ZOL was identified by NDC or HCPCS codes C9115 or J3487. Members with evidence of use of oral tiludronate, IV ibandronate, oral or IV etidronate, or yearly ZOL identified by National Drug Code (NDC) or HCPCS codes (IV ibandronate: HCPCS C9229, J1740; IV etidronate: J1436; yearly ZOL: J3488, Q4095) at any time during the analysis period were also excluded.
Patients were permitted to have variable follow-up periods with a maximum follow-up period of 7 years. The duration of follow-up was calculated as the number of days from the index date until disenrollment from the health plan (including due to death) or the end of the analysis period (December 31, 2007). Patients who died during an inpatient admission were identified from facility claims in the database affiliated with OptumInsight to distinguish disenrollment because of death vs disenrollment because of other factors that may not have been reported in the data.
Patient demographic and treatment characteristics
Age was determined as of the index year, and insurance type (commercial or Medicare) and sex were determined from enrollment data. A Charlson-Quan comorbidity score was calculated based on the presence of diagnosis codes on medical claims in the pre-index periodCitation23. The use of oral BPs (e.g., alendronate, ibandronate, and risedronate) during the pre-index period was identified from pharmacy claims. Chemotherapy received during the post-index period was identified by HCPCS and procedure codes.
Treatment discontinuation was defined as the first appearance of a gap of >45 days between ZOL treatments. The date of discontinuation was defined as the service date for the last ZOL claim before the gap. Persistence was defined as the number of days from the first date of treatment with ZOL until the date of discontinuation, disenrollment, or end of analysis period (December 31, 2007), using the earliest of these three dates. Patients were assigned to a persistency category based on length of treatment with ZOL (31–90 days, 91–180 days, 181–365 days, or 366–546 days).
Analysis outcomes
Patient mortality was assessed during the post-index period. Occurrence of death was identified from facility claims based on patient discharge status for death on facility claims or a diagnosis code for death (ICD-9-CM 798.xx) on a facility or physician claim. The time to mortality was calculated as the number of days between the index date and the death date. Because only one of the two health plan databases used for this study included mortality data, patient mortality could only be determined for a sub-set of patients. Fractures were identified from medical claims based on the presence of ICD-9-CM diagnosis codes () or CPT procedure codes for surgery to the bone (). The occurrence of SREs, including pathologic fracture, surgery to the bone, spinal cord compression, or radiation to the bone, was also determined in the pre- and post-index periods. Spinal cord compression was identified from medical claims based on ICD-9-CM diagnosis code 336.9, and radiation to the bone was identified from medical claims based on CPT procedure codes 77401–77406, 77418, 77422–77423, 77407–77411, 77412–77416, and 79101.
Table 1. ICD-9-CM codes to identify fractures.
Table 2. CPT procedure codes to identify fractures.
Statistical analysis
Unadjusted bivariate comparisons of baseline characteristics and outcome measures were performed using appropriate tests (e.g., t-test, Mann-Whitney U test, chi-square test) based on the distribution of the measure. As the length of follow-up varied due to censoring, incidence rates and mortality rates were calculated using stptime (Stata® version 9.2; StataCorp, College Station, TX). Stptime is a survival analysis method that computes and tabulates the person-time and incidence rate (calculated by the number of events such as an SRE or death divided by the person-time). Due to variability in the length of follow-up periods, study outcomes were measured as risk per 100 person-years. This test is similar to the log-rank test, except that the ordinal ranking across persistency categories was considered. Multivariate analysis adjusting for covariates was conducted using the Cox proportional hazards model, adjusting for sex, age, year of index date, geographic region, pre-index Charlson-Quan comorbidity score, pre-index evidence of oral BP use, and pre-index SREs. Analyses were conducted using version 10.0 of Stata statistical software (StataCorp).
Results
Patients
A total of 9874 patients were identified from the database for inclusion in this analysis (). Patients with evidence of ZOL use on or following the index date were assigned to the ZOL cohort (1090 patients; 11.0%), and patients without evidence of ZOL use on or following the index date were assigned to the no IV-BP cohort (8784 patients; 89.0%). Mean age was similar between cohorts (p = 0.2218). Compared with patients in the no IV-BP cohort, patients in the ZOL cohort were more often male (p = 0.0260), and were more likely to have commercial insurance than Medicare Advantage insurance (p < 0.0001) (). No statistically significant difference was observed for length of mean follow-up between cohorts (p = 0.2644). Use of oral BP therapy during the pre-index period was similar between cohorts (p = 0.0870), and chemotherapy was more common among patients in the ZOL cohort compared with patients in the no IV-BP cohort (p < 0.0001) ().
Table 3. Patient demographics and clinical characteristics.
Clinical outcomes
The percentage of patients remaining fracture-free over a 2-year period was compared between the ZOL and no IV-BP cohorts. Overall, without controlling for other factors, treatment with ZOL reduced the relative fracture risk by 40% compared with no IV-BP (). The benefit of treatment with ZOL, in terms of lower fracture risk, appears to be greater with longer treatment duration (). For the sub-set of patients included in a survival analysis (n = 550 ZOL; n = 4512 no IV-BP), patients treated with ZOL had a significantly lower mean (95% confidence interval) mortality vs untreated patients (38.6 [32.4, 46.0] vs 46.8 [44.2, 49.6] deaths/100 person-years; p = 0.038).
Figure 2. Kaplan-Meier curves showing time course of proportion of patients fracture-free for the ZOL and no IV-BP cohorts. Index date represents the date of bone metastasis diagnosis for the no IV-BP cohort and the date of first ZOL treatment for the ZOL-treated cohort. IV-BP, intravenous bisphosphonate; ZOL, zoledronic acid.
Treatment duration and clinical outcomes
Based on the length of uninterrupted treatment with ZOL, patients were assigned to the following persistency categories: 31–90 days (n = 300), 91–180 days (n = 138), 181–365 days (n = 84), and 366–546 days (n = 26). Of patients in the ZOL cohort, only 4.0% received ZOL for longer than 1 year. The risk of fracture (per 100 person-years) for the ZOL and no IV-BP cohorts was compared as a function of treatment persistency. The risk of fracture, without controlling for other factors, was consistently lower with increasing duration of ZOL therapy (). Even short durations of ZOL therapy (31–90 days) resulted in a substantially lower fracture risk compared with no IV-BP. However, benefits were more profound with persistent ZOL therapy (≥366 days) ().
Figure 3. Comparison of the risk of fractures (per 100 person-years) between the ZOL and no IV-BP cohorts as a function of ZOL treatment persistency. IV-BP, intravenous bisphosphonate; ZOL, zoledronic acid.
Analysis outcomes were also evaluated using Cox proportional hazard models to adjust for differences in demographic and clinical characteristics among patients (). Significant covariates included in the model were sex, age, year of index date, geographic region, pre-index Quan-Charlson Comorbidity Index score, history of oral BP use, and history of SREs. Even short-term (31–90 days) treatment with ZOL had a significantly lower fracture risk by 47% compared with no IV-BP (p = 0.005) (). Longer persistency (366–546 days) with ZOL therapy was associated with 73% greater reductions in fracture risk; however, small sample size limited statistical power at the later time points ().
Table 4. Correlation of risk of fracture with treatment persistency (adjusted)a.
Early treatment and clinical outcomes
Fracture risk (per 100 person-years) as a function of interval (delay) between diagnosis of bone metastases and initiation of ZOL treatment was evaluated and included patients who initiated ZOL > 30 days after diagnosis of bone metastases, even though these patients were excluded from all other analyses. Patients who initiated ZOL treatment immediately after bone metastases were diagnosed had a 1.6% risk of developing fractures (). Initiating ZOL therapy after longer time periods, however, was associated with a substantially higher fracture risk, with time periods >60 days associated with an ∼25% risk of fracture ().
Figure 4. Risk of fracture (per 100 person-years) as a function of interval (delay) between diagnosis of bone metastases and initiation of ZOL therapy. ZOL, zoledronic acid.
Discussion
Patients with bone metastases from lung cancer are at risk for SREs, including fracture, which can cause considerable morbidity, adverse effects on quality-of-life, and increased mortalityCitation1. Treatment with ZOL, an IV-BP, effectively delays the onset and reduces the incidence of SREs in patients with bone metastases from multiple tumor types including breast, prostate, lung, and other solid tumorsCitation15–20. The current retrospective analysis assessed the effect of treatment initiation and duration with ZOL on fracture risk in patients with bone metastases from lung cancer. Patients treated with ZOL had significantly lower risks of fracture (p = 0.005) compared with patients in the no IV-BP cohort. Patients with longer ZOL persistency consistently achieved better outcomes. For example, patients treated monthly with ZOL for ≥12 months had a 57% lower fracture risk compared with patients who did not receive IV-BP therapy. Patients who initiated ZOL shortly after diagnosis of bone metastasis had significantly fewer fractures compared with patients in whom therapy was not initiated until ≥60 days after diagnosis (p < 0.0017). Collectively, these data support the current ZOL label and clinical recommendations that ZOL be initiated as soon as bone metastases are diagnosed and be continued for as long as tolerableCitation24.
The concept of early and continuous ZOL treatment is also supported by emerging data suggesting that, in addition to preserving skeletal health, ZOL therapy may positively affect the disease course in patients with lung cancer. In a post-hoc analysis of patients with bone metastases from NSCLC, ZOL-treated patients showed trends toward prolonged time to first SRE, reduced annual SRE incidence, and longer median survivalCitation25. Moreover, ZOL-mediated normalization of N-telopeptide of type I collagen (NTX), a marker of bone resorption that is associated with increased risks of SREs and death, resulted in significantly decreased risk of death (p = 0.024) in a retrospective analysis of patients with NSCLC with bone metastasesCitation25–27. In a recent prospective study, patients with lung cancer and bone metastases treated with ZOL in addition to chemotherapy had statistically significantly longer survival compared with those receiving chemotherapy only (p < 0.01)Citation28. It has been suggested the survival benefits may be attributed to direct and indirect anti-cancer activity of ZOL.
Pre-clinical data in lung cancer models have demonstrated that BPs can impact multiple steps in the metastatic process, including suppression of tumor growth, promotion of apoptosis, inhibition of angiogenesisCitation29, and stimulation of an anti-cancer sub-set of γδ T-cellsCitation30–32. Accumulating evidence suggests that BPs can inhibit tumor cell proliferation and induce apoptosis in a broad range of human cancer cell linesCitation33–36. Bisphosphonates have also been shown to alter the course of disease progression in mouse model systems of human cancersCitation37–50. Moreover, ZOL treatment reduced tumor growth and improved survival in a mouse model of NSCLCCitation51. These data, along with data from other cancer models, provided the rationale to investigate the anti-cancer properties of ZOL in the clinical setting, and the results reported to date have been encouraging.
The first efficacy data from clinical trials investigating the potential anti-cancer effects of BPs have recently become available. For example, in a recent trial, patients (n = 144) receiving chemotherapy for lung cancer with bone metastases were treated with ZOL if they had bone pain (n = 87) or with chemotherapy alone if their bone metastases were asymptomatic (n = 57)Citation28. Patients receiving ZOL had significantly longer survival (578 vs 384 days; p < 0.001) and time to disease progression (265 vs 150 days; p < 0.001) compared with patients receiving chemotherapyCitation28. The number of cycles of ZOL treatment was positively correlated with time to disease progression, supporting the potential for greater benefits with longer treatmentCitation28. In multivariate analyses, ZOL therapy was associated with a 39% reduction in the risk of death (p = 0.015) and a 61% reduction in the risk of disease progression (p < 0.001) compared with chemotherapy aloneCitation52. Moreover, ZOL treatment was also associated with a 2-fold higher rate of tumor response at the primary site and a 38% lower rate of progressive disease in the skeleton compared with chemotherapy aloneCitation52. Furthermore, a retrospective audit of 114 patients with bone metastases from NSCLC treated with or without ZOL between 2004 and 2009 revealed a significant survival benefit from ZOL treatment (median overall survival of 34 weeks vs 19 weeks without ZOL; p = 0.01)Citation53. In addition to the clinical data in patients with lung cancer, evidence for the anti-cancer activity of BPs is accumulating in other cancer typesCitation54. For example, evidence from large, randomized, phase 3 trials in patients with breast cancer is mounting, and pilot studies in patients with bladder cancer, multiple myeloma, and advanced solid tumors are also promisingCitation55–60.
Although claims data are valuable for the examination of healthcare outcomes and treatment patterns, they are primarily collected for the purpose of claims and payments. Therefore, there are certain limitations associated with the use of claims data. Results presented are based on analysis of observational data wherein patients were not randomized to treatment, time of treatment initiation, or length of persistency. The presence of a diagnosis code on a medical claim may in some cases not indicate disease presence, as the diagnosis code could be incorrectly coded or included as a rule-out criterion rather than actual disease. Additionally, some known prognostic factors (e.g., clinical and disease-specific parameters) are not readily available in claims data, and therefore cannot be controlled for in analyses such as the one presented herein. For example, the lack of data on histological sub-types (e.g., NSCLC or small cell lung cancer) represents a well-known limitation of the ICD-9-CM coding system. It is also not possible to determine from claims data whether treatment interruptions were physician-directed or true non-adherence. For instance, an adverse effect, if severe enough, may necessitate an interruption in therapy and thus over-estimate discontinuation. Similarly, it is recommended that dosing of ZOL be adjusted downward in patients with impaired renal function; however, laboratory values were not available for the full analysis sample and were not used in this analysis. Furthermore, this database contained no real-world data on the monoclonal antibody against the receptor-activator of nuclear factor kappa B ligand, denosumab, which is now also approved for the prevention of SREs in patients with bone metastases from solid tumors in the US and Europe, as no long-term data for denosumab are currently available in this population outside the clinical trial setting.
Despite these limitations, claims-based analyses may be valuable in providing real-world data to help healthcare providers make informed clinical decisions regarding their patients. Although it is not possible to directly compare clinical trial data with data from a claims-based analysis, both types of data for ZOL indicate that treatment with ZOL reduces the skeletal morbidity rate and delays the time to SREs in patients with bone metastases from multiple cancer types, including lung cancer. The current retrospective analysis provides further evidence for the benefit of early and persistent treatment with ZOL in patients with bone metastases from lung cancer.
Transparency
Funding
Novartis Pharmaceuticals Corporation provided funding for this research and financial support for medical editorial assistance.
Financial/other relationships
HJH and AT are employees of OptumInsight, a company that received funding from Novartis to conduct the research. SK was employed by Novartis Pharmaceuticals Corporation at the time this manuscript was written.
Acknowledgments
We thank Payal N. Gandhi, PhD, ProEd Communications, Inc., for her medical editorial assistance with this manuscript. Presented in part at the ECCO 15–34th ESMO Multidisciplinary Congress, September 20–24, 2009, Berlin, Germany.
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