Bone-Modifying Agent Utilization: An Analysis in Patients With Metastatic Cancer and Bone Involvement at an NCI-Designated Cancer Center

J Clin Pathways. 2023;9(2):19-24. doi:10.25270/jcp.2023.03.01

Bone metastases are prevalent in advanced cancer and represent a significant burden to both patients and the health care system.¹ Complications from bone metastases include pain, decreased performance status, decreased quality of life, and skeletal-related events (SREs; defined as events necessitating surgery or radiation including spinal cord compression, hypercalcemia of malignancy, and pathological fractures).^2,3

Osteoclast inhibition has become a vital component in the management and prevention of complications for patients with bone metastases.⁴ Two general classes of bone-modifying agents (BMAs) are widely administered: bisphospho­nates and RANK ligand inhibitors. Guidelines support the use of both zoledronic acid (ZA; a bisphosphonate administered intravenously) and denosumab (DB; a RANK ligand inhibitor administered subcutaneously) to reduce SREs for pa­tients with metastatic cancer and bone involvement.^5,6 In general, the selection of an osteoclast inhibitor is influenced by tumor type, patient and provider prefer­ence, frequency of administration, and comorbidities. Practice patterns have been guided primarily by evidence from metastatic breast and prostate cancer, where up to 70% of patients have bone metastases, as well as multiple myeloma, where bone involvement is universal.³

In metastatic breast cancer, the recommended schedule of administration for ZA has changed based on the results from 2 randomized phase 3 trials show­ing similar efficacy in SREs between every 12 weeks (Q3) or 3 to 4 weeks (Q1).^7,8 For multiple myeloma, the Z-MARK study specifically addressed the dosing interval for ZA using a biochemical marker for bone resorption, urinary N-telopeptide type 1 collagen, as a surrogate for SRE.⁹ Similarly, a contemporary, open-label randomized trial evaluating ZA administration frequency in breast cancer, prostate cancer, and multiple my­eloma showed no difference in primary outcome of SREs.¹⁰ The lack of indication for DB in multiple myeloma accounts for the vast majority of patients with this disease state receiv­ing ZA.^11,12 A pooled meta-analysis of 8 studies comprising 2,878 patients suggested that de-escalation to a Q3 strategy for ZA was noninferior to the Q1 dosing interval.¹³ These large trials have led to American Society of Clinical On­cology (ASCO) guideline updates in multiple myeloma and metastatic breast cancer endorsing the Q3 schedule.¹⁴ Up­take of these guideline recommendations in practice has not been characterized.

Although ZA and DB have a similar scope of indications, they vary greatly in cost. A cost-effectiveness analysis study demonstrated that Q3 ZA was more cost effective than Q1 DB in women with metastatic breast cancer.¹⁵ The financial implications of bone metastases in patients across all tumor types has not been fully explored. Due to technological ad­vances in diagnosis and treatment, patients are living longer with cancer, and the price of innovation and a larger patient pool contribute to the rising cost of cancer care.^16,17 Drug costs have dominated the public sphere, accounting for 10% of expenditures in 2017 based on reports from the Centers for Medicare & Medicaid Services (CMS).¹⁸ A substantial portion of spending in oncology can be classified as “low-value” care (eg, overutilization of medications that do not provide meaningful improvements in cancer outcomes). Trends in BMA utilization may identify areas to improve guideline adherence and value in cancer care. Our study ex­plores the practice patterns in BMA utilization at a National Cancer Institute–designated cancer center and highlights po­tential cost savings. Some of these findings were previously presented in the form of a conference abstract.¹⁹

Assessments

We performed a retrospective review of BMA utilization at the Seattle Cancer Care Alliance, University of Washington, during the fiscal years 2015 to 2020. Institutional Review Board approval was obtained to perform this study.

Data Abstraction

Billing data from 2015 to 2020 on dispensed units of ZA and DB injections was extracted from a Structured Query Language (SQL) database. Extracted data included patient record number, administration dates, agent (ZA or DB), pri­mary medical oncology provider, associated disease group, and cancer primary diagnosis codes. The data were exported into a spreadsheet for data cleaning and statistical analysis, and results were displayed using data-visualization software. In cases where the disease group classification and primary diagnosis codes were not identical (eg, bone cancer in a breast cancer disease group), manual abstraction was utilized to assure the disease group classifications were correct. Patients receiving BMA for other indications, such as osteoporosis, were excluded.

Although clinical trials rigorously tested a Q1 vs Q3 ad­ministration of ZA, in clinical practice, it is not always pos­sible to adhere to such rigorous timings. To account for this, we developed a method to classify a given patient as either Q1 or Q3. Additionally, some patients transitioned from one administration schedule to another, and this was accounted for by our method.

BMA Frequency: Q1 vs Q3 Classification

For every administration except the last, we calculated the number of days to next administration. For the last admin­istration, the calculation was based on the difference of days between the last administration and the second to last ad­ministration. A histogram of this distribution was bimodal as expected, and an optimal cutoff to distinguish between Q1 and Q3 administration was determined to be 60 days. We then classified each individual administration as either a Q1 or Q3 administration based on this cutoff.

Patients were classified to one of the following groups: Q1 patient, Q3 patient, Q1 to Q3 transition, Q3 to Q1 transition, or indeterminant.

A Q1 patient was defined by meeting any of the follow­ing requirements: only Q1 administrations; at least 3 admin­istrations, all of which were Q1 with the exception of 1 Q3 administration; at least 10 administrations, all of which were Q1 with the exception of 2 Q3 administrations; and at least 15 administrations, all of which were Q1 with the exception of 3 Q3 administrations.

A Q3 patient was classified using identical logic to the Q1 patient group except for Q1 and Q3 being reversed. If a patient did not meet the above criteria for being automati­cally classified as a Q1 or Q3 patient, their classification was indeterminant and they were then manually classified by an investigator. This happened for 72 of 258 patients.

Q1 to Q3 transition patients were defined as patients who had greater than 5 total administrations and whose first one-third to two-thirds of their total administrations were given as Q1, with the remaining administrations given as Q3. Q3 to Q1 transition patients were defined using identi­cal logic to the Q1 to Q3 transition group except for Q1 and Q3 being reversed. Indeterminant patients were classi­fied as either those with fewer than 5 total administrations with no greater than 3 administrations in either Q1 or Q3, or patients with greater than 15 administrations who met requirements for both transition classifications (ie, switched but did not commit to dosage patterns).

Determination of Costs and Potential Cost Savings

We estimated the financial impact of BMA utilization at our institution using wholesale acquisition (WAC) from CMS Average Sale Price Drug Pricing Files and administration costs for each drug (Medicare Billing Rates). Institutional in­fusion costs were accounted for; however, individual lab costs were not considered. We applied the costs to project potential savings using various model assumptions.

BMA Practice Patterns: Agent Selection

During the fiscal years 2015 to 2020, we identified 1,421 patients who received 14,545 administrations of a BMA. Our study identified 1,003 patients who received ZA with 8,237 unique administrations. Similarly, 536 patients received DB with 6,308 unique administrations. Some patients received both ZA and DB and are counted in both of the patient cate­gories. Figure 1A shows the trend in ZA and DB administra­tions over time. Proportionately, there were more ZA admin­istrations compared to DB during each fiscal year. Figure 1B further classifies BMA utilization across disease groups.

Average Sale Price Drug Pricing Files and administration costs for each drug (Medicare Billing Rates). Institutional in­fusion costs were accounted for; however, individual lab costs were not considered. We applied the costs to project potential savings using various model assumptions.

BMA Practice Patterns: Frequency of Adminstration

In metastatic breast cancer, we observed a trend toward more Q3 administration and less Q1 administration over time, with a total of 27 patients transitioning from Q1 to Q3 ZA admin­istration. The highest uptake to Q3 administration occurred around fiscal year 2017, coinciding with the 2017 ASCO update on BMAs in metastatic breast cancer (Figure 2). Similarly, in multiple myeloma, our findings show more Q3 administration over time compared to Q1 administration of ZA, with a total of 33 patients transitioning to Q3.

Although this was not the intent of the study, it was noted that there was a consistent increase in the number of Q3 DB administrations from 2015 to 2020 (7.45% to 15.89%). However, it should be noted that the total number of Q3 DB administrations constituted a very small percentage of the overall number of DB administrations (12.7%).

BMA Cost Implications

Based on WAC, the mean cost per administration of DB and ZA from 2015 to 2020 was $2,079.84 and $59.94, re­spectively. After accounting for administrative costs ($16.94 for DB vs $72.80 for ZA), we calculated the total costs for BMA utilization (Table). Total expenditures for fiscal year 2015 to 2020 was $1.3 million for ZA and $13.0 million for DB. Cumulatively, $14.3 million was spent on BMA from fiscal year 2015 to 2020, with over 90% of costs attributable to DB.

Finally, we projected the potential cost savings using a model assumption that all patients receive Q3 BMA across various scenarios. First, we evaluated the potential cost sav­ings for patients with metastatic breast cancer where there is strong evidence and national guideline recommendations for Q3 ZA dosing. If all patients with metastatic breast can­cer received Q3 ZA during our study period, we calculated a potential savings of approximately $260,000. Similarly, ASCO supports Q3 dosing in multiple myeloma, and the projected cost savings if all these patients received Q3 ZA was estimated as $313,702.

To understand the magnitude of effect for Q3 ZA ad­ministration in all tumor types, we projected costs savings of nearly $1 million for the entire cohort under the Q3 assump­tion. We estimated a potential cost savings of over $10 million if both DB and ZA were given as Q3 schedules. Finally, we also modeled potential savings if 80% of patients receiving DB received Q3 ZA instead (accounting for an estimated 20% of patients who could not be moved due to a creatinine clearance < 30 mL/min or intolerance) and determined a cost savings of nearly $10 million.

Although there are no definitive guidelines for BMA selec­tion and dosing schedule for most tumor types, large stud­ies evaluating dosing intervals in metastatic breast cancer and multiple myeloma have led to national guideline updates for the use of BMA in these tumor types.^12,14 Our institution has demonstrated uptake of guidelines for BMA frequency recommendations in metastatic breast cancer and multiple myeloma, but this has not been universal. Though the high­est transition to Q3 ZA administration correlated with the ASCO 2017 guidelines, the trend predates this update and correlates with the release of phase 3 trials supporting this practice. We also noted that prescribing patterns of ZA and DB have not changed in the fiscal years 2015 to 2020 in the entire cohort. However, considering that there have been more Q3 administrations for ZA during this time period, the relative stability of the proportion of ZA to DB prescriptions (60:40) reveals that more patients are receiving ZA compared to DB. We found that this is driven largely by the shift in prescribing patterns in breast cancer.

For other tumor types, our study shows that while guide­line adherence to BMA use has improved over time in our institution, the uptake is not universal and is less common. These findings have key financial implications and present an opportunity for improvement in value in cancer care.

Despite robust data addressing alternative dosing intervals, change to Q3 ZA is not routinely adopted but may be a reasonable option from a value perspective given the findings from the CALBG 70604 trial.¹⁵ While our study evaluated the trends in frequency of BMA administration and potential cost savings associated with Q3 administration, the greater impact on cost is driven by DB.

Although Q3 administration of DB is not yet supported by national guidelines, there is emerging literature and ongo­ing trials that support this regimen. The Canadian open-label study REaCT-BTA (NCT02721433)²⁰ evaluated standard of care for BMAs (pamidronate, ZA, or DB) and impact on health-related quality of life. Patients were randomly assigned to Q1 or Q3 dosing for 1 year. Results were presented at the European Society for Medical Oncology meeting in May 2019 and reported that both treatments provided similar quality of life, global health status, and pain scores. Important­ly, no differences in SREs (secondary endpoint) were noted, suggesting that de-escalation of ZA and DB are reasonable treatment approaches, though admittedly it was underpow­ered to assess this outcome.

An ongoing European trial called SAKK 96/12, or RE­DUSE (NCT02051218), is an open-label study with planned enrollment of 1,380 participants evaluating the primary out­come of time to first symptomatic SRE. The standard arm will receive Q1 DB, whereas the experimental arm will ini­tially receive Q1 dosing and transition to Q3. The study has completed accrual, and the anticipated results of this study will further strengthen the strategy of de-escalation and pro­mote widespread uptake of this practice.

Finally, optimal duration of BMA treatment in metastatic cancer remains unexplored. National guidelines maintain a recommendation for indefinite use in patients with meta­static breast cancer, though they affirm that weighing ben­efit and risk of long-term use should be part of informed decision-making. Data from patients with osteopenia show the long-standing bone-protective effects after a single dose of bisphosphonate, questioning the need for indefinite BMA therapy in patients with metastatic cancer.²¹ Patients with cancer are living longer, and long-term data on BMA safety and efficacy in this population is vital in determining de-escalation strategies, including drug holidays.

With the goal of optimizing patient health and qual­ity improvement, clinical pathways have emerged as a tool to encourage guideline adherence. In March 2017, ASCO released its Criteria for High Quality Clinical Pathways to evaluate adherence and implementation of pathways.²² Value Pathways is a prominent leader in this national effort and promotes quality measures by incorporating the National Comprehensive Cancer Network clinical practice guide­lines with the US Oncology Network.²³ This tool has iden­tified variations in management and cost savings through implementation of clinical pathways. For example, among the Medicare population, a 2018 study estimated a cost sav­ings of more than $3 million through use of Value Pathways, primarily driven by a reduction in medication costs.²⁴ As the cost of oncology drugs continues to rise, adopting clinical pathways can streamline the integration of evidence-based best practices to advance value in cancer care. Currently, our institution does not have standard value pathways for BMA utilization, but we hope our findings will spur quality initiatives in our institution to utilize clinical pathways to advance delivery of high-value care.

Our study provides early insight into the economic impact of widespread use of Q3 dosing for DB and ZA. However, inherent to the nature of a retrospective review, the nuances of clinical practice cannot be captured. Clinical decision-making is not accounted for in our modeling assumption for cost savings. For example, patients with renal dysfunc­tion may be appropriately given DB over ZA. Even so, these scenarios are not common, and our findings are applicable to the majority of patients with metastatic cancer with bone involvement. Our study does not evaluate the quality of life and financial impact of potential adverse events experienced during the course of BMA therapy, such as osteonecrosis of the jaw and atypical fractures.

Data demonstrate that duration and cumulative dose of BMA correlate with the incidence of these adverse events, and data are needed to evaluate whether administration fre­quency could minimize these complications. Clinical out­comes are not assessed in our study, and we assume that SREs are generalizable to our population. Meta-analyses show comparable rates of SREs across various cancer centers,^13,25 and we believe our single-center experience is reflective of the general population.

Admittedly, our findings are primarily descriptive and hypothesis generating. Still, we believe these results high­light key gaps for future investigations in the management of patients with metastatic cancer. We acknowledge that our model assumes that the de-escalation strategy supported by guidelines in multiple myeloma and breast cancer can be ex­trapolated to all solid tumor types. Future studies across all solid tumor types are needed to confirm this de-escalation strategy and promote universal use of the Q3 dosing interval. We hope these results serve as a launching point to explore barriers to guideline adherence and empower clinicians, re­searchers, guideline makers, and the larger cancer community to unify around actionable, data-driven strategies to reach the common goal of improving patient outcomes and value for patients with metastatic cancer.

In our institution, we found that BMA prescribing patterns from 2015 to 2020 showed no change in relative ZA and DB utilization, though there was a trend toward increased ZA and decreased DB in breast cancer. There was a transition in practice patterns to adopt Q3 ZA administrations over time; however, the uptake of this has been incomplete. Clini­cal pathways for BMAs could facilitate the wider adoption of the Q3 regimens and translate into significant cost savings.

Authors:  Poorni M. Manohar, MD^1,2; Kyle E. Bastys²; Micah Tratt¹; Julie Gralow, MD, FACP, FASCO³; Keith D. Eaton, MD, PhD^1,2

Affiliations: ¹University of Washington/Seattle Cancer Care Alliance, Seattle, WA; ²Fred Hutchinson Cancer Research Center, Seattle, WA; ³American Society of Clinical Oncology, Alexandria, VA

Address correspondence to: 

Poorni M. Manohar
Seattle Cancer Care Alliance
825 Eastlake Ave N, LG-540
Seattle WA 98109-1024
Phone: 400-478-6330
Email: manoharp@uw.edu

Disclosures: K.D.E. has received research grants from Mirati Therapeutics. The remaining authors disclose no financial or other conflicts of interest.