Treatment dynamics of bone-targeting agents among men with bone metastases from prostate cancer in the United States.

PURPOSE: To examine the dynamics of treatment with 2 bone-targeting agents (BTAs)-denosumab and zoledronic acid-among men with bone metastases from prostate cancer. METHODS: Using electronic health record data from oncology practices across the US, we identified prostate cancer patients diagnosed with bone metastasis in 2012/2013 without evidence of BTA use within 6 months prior to diagnosis. We examined the risk and predictors of BTA initiation, interruption, and re-initiation. RESULTS: Among 897 men diagnosed with prostate cancer, the cumulative incidence of BTA initiation after bone metastasis diagnosis was 34% (95% confidence interval [CI], 31-37%) at 30 days, 64% (95% CI, 61-68%) at 180 days, and 88% (95% CI, 85-91%) at 2 years. Denosumab was initiated more frequently than zoledronic acid. Men with diabetes, more bone lesions, history of androgen deprivation therapy, or no hospice enrollment were more likely to initiate treatment. Following initiation, the cumulative incidence of treatment interruption was 17% (95% CI, 14-19%) at 60 days and 70% (95% CI, 66-74%) at 2 years, with interruption more likely among patients receiving emerging therapies for prostate cancer or enrolling in hospice. The cumulative incidence of re-initiation following interruption was 36.3% (95% CI, 32.7-40.2%) at 15 days, 49.8% (95% CI, 45.9-54.1%) at 30 days, and 81.0% (95% CI, 77.5-84.7%) at 1 year. CONCLUSIONS: Bone-targeting agent therapy is initiated by the majority of men living with bone metastases following a prostate cancer diagnosis; however, the timing of initiation is highly variable. Once on treatment, gaps or interruptions in therapy are common.

Design and Rationale of the Metastatic Renal Cell Carcinoma (MaRCC) Registry: A Prospective Academic and Community-Based Study of Patients With Metastatic Renal Cell Cancer.

The Metastatic Renal Cell Cancer Registry, a large, nationally representative, prospective registry of patients with metastatic renal cell carcinoma (mRCC), aims to understand real-world treatment patterns and outcomes of patients with mRCC in routine clinical practice across the United States. This observational study is designed to enroll 500 patients with previously untreated mRCC from approximately 60 academic and community treatment sites; as of December 7, 2016, 500 patients have enrolled at 54 sites. Key endpoints include real-world data on reasons for treatment initiation and discontinuation; treatment regimens; disease progression; patient-reported outcomes; and healthcare resource utilization in this patient population.

Management of chemotherapy-induced neutropenia: measuring quality, cost, and value.

Treatment-associated neutropenia continues to represent the most common dose-limiting toxicity of cancer chemotherapy. It often leads to fever and infection, prompting hospitalization and occasionally resulting in serious morbidity, and even mortality, despite modern broad-spectrum antibiotic treatment and supportive care. Neutropenia and its complications may also lead to chemotherapy dose reductions, treatment delays, or early treatment termination, compromising disease control and the potential for cure. NCCN Clinical Practice Guidelines in Oncology recommend administration of primary prophylaxis with a myeloid growth factor in patients receiving regimens associated with a high risk for febrile neutropenia, and consideration of prophylaxis in patients receiving lower-risk regimens who have other risk factors that might place them at higher risk for febrile neutropenia. Although these agents have been shown to be effective and safe in numerous randomized controlled trials, they are expensive and contribute significantly to increasing health care costs. Regulatory agencies and guideline organizations do not currently address the issue of cost. However, with the relentless increase in health care use and current efforts to reform health care, it has become increasingly important to assess both the cost and the net benefit of interventions related to an episode of care in order to compare the overall value of therapeutic options. This article defines and discusses the intersection of quality, costs, and value in the context of prophylactic myeloid growth factor use in patients with cancer receiving myelosuppressive chemotherapy.

Treatment selection in metastatic renal cell carcinoma: more confusion or a path forward?

Meaningful progress has been realized in the treatment of metastatic renal cell carcinoma with the recent approval of a number of new agents; more new agents are on the horizon. Despite the recent completion of many clinical trials that have changed or will change practice, many questions remain. In this manuscript, we highlight the most noteworthy developments in the first- and second-line treatment of metastatic renal cell carcinoma, as these are the areas of greatest change. We also emphasize ongoing trials and those areas that are most in need of study in order to move the field forward. Although more data are needed, exciting progress is being made.

Will biosimilars gain momentum?

Biosimilars, also known as follow-on biologics, continue to be an area of great interest in oncology because of the potential cost savings and improved access related to their use, yet significant confusion remains regarding their introduction in the United States. The regulatory and legal hurdles remain poorly defined, and companies producing branded products have been battling their introduction. The European Union provided a pathway for approval in 2004, with various agents reaching the market since that time. It is important to understand the nuances of the discussion and experiences and for clinicians and policy makers to take an active part in defining the role of biosimilars. Several outstanding questions remain, including the degree to which physiochemical, biologic, quality, and clinical end points must be demonstrated in clinical trials compared with the use of analytic data for approval; whether off-label indications should be embraced; and the regulatory rules around areas such as marketing and interchangeability. This article highlights tbo-filgrastim, an agent currently marketed as a biosimilar in Europe, because its pending introduction in the US market provides insights into the potential of these agents.

Delivering affordable cancer care in high-income countries.

The burden of cancer is growing, and the disease is becoming a major economic expenditure for all developed countries. In 2008, the worldwide cost of cancer due to premature death and disability (not including direct medical costs) was estimated to be US$895 billion. This is not simply due to an increase in absolute numbers, but also the rate of increase of expenditure on cancer. What are the drivers and solutions to the so-called cancer-cost curve in developed countries? How are we going to afford to deliver high quality and equitable care? Here, expert opinion from health-care professionals, policy makers, and cancer survivors has been gathered to address the barriers and solutions to delivering affordable cancer care. Although many of the drivers and themes are specific to a particular field-eg, the huge development costs for cancer medicines-there is strong concordance running through each contribution. Several drivers of cost, such as over-use, rapid expansion, and shortening life cycles of cancer technologies (such as medicines and imaging modalities), and the lack of suitable clinical research and integrated health economic studies, have converged with more defensive medical practice, a less informed regulatory system, a lack of evidence-based sociopolitical debate, and a declining degree of fairness for all patients with cancer. Urgent solutions range from re-engineering of the macroeconomic basis of cancer costs (eg, value-based approaches to bend the cost curve and allow cost-saving technologies), greater education of policy makers, and an informed and transparent regulatory system. A radical shift in cancer policy is also required. Political toleration of unfairness in access to affordable cancer treatment is unacceptable. The cancer profession and industry should take responsibility and not accept a substandard evidence base and an ethos of very small benefit at whatever cost; rather, we need delivery of fair prices and real value from new technologies.

Biosimilars: are they ready for primetime in the United States?

The introduction of alternative versions of biologic products, also known as biosimilars, into the United States market has been gaining increasing visibility as patents for many agents are nearing expiration. Unlike generics, which are regulated under the Hatch-Waxman legislation passed in 1984, the approval process for biosimilars in the United States has not been defined. In 2004, the European Union established a regulatory pathway for these agents, and the FDA is now following suit. The economic implications are large, with $66.9 billion spent on the top 20 biologics in 2009. Of the top 10 biologics, 6 are routinely used in oncology. As the regulatory requirements are debated, several critical issues must be resolved. The most obvious is that the agents must be shown to be comparable to the original biologic they intend to replace. Knowledge of pharmacokinetic parameters alone will not be adequate, but the amount of clinical data required by the FDA remains unclear. The regulations will define the ease with which a biosimilar can be brought to market, and the associated costs of trials will influence the ultimate price of the medications. Balancing the needs of the relevant stakeholders is critical to ensure patient safety while controlling costs, improving access, and encouraging innovation. This is not an easy balance to strike.

Breast cancer screening with mammography.

There has been a great deal of controversy regarding the change in breast cancer screening recommendations released by the US Preventive Services Task Force in November 2009. Despite limited new data, the Task Force changed their previous recommendations delaying initial screening of asymptomatic women from age 40 to age 50 and recommending biennial rather than annual breast cancer screening. It is important to fully understand the nuances of the analysis and modeling upon which the revisions were based in order to accurately inform patients of the risks and benefits of breast cancer screening. Several new studies as well as additional guidelines have also been released over the past year which further inform the debate, and a number of commentaries have helped to place the risks and benefit in clinical and societal context.

Experience of the National Cancer Institute Community Cancer Centers Program on Community-Based Cancer Clinical Trials Activity.

PURPOSE: A goal of the National Cancer Institute Community Cancer Centers Program (NCCCP) was to improve cancer research capacity in community settings. We examined research capacity development during the pilot phase of the NCCCP within the context of national trends in clinical trial activity with respect to the number and phase of trials, total accrual, and accrual of underserved populations. MATERIALS AND METHODS: We examined self-reported data from NCCCP sites during 2007 to 2010, supplemented with data from the National Cancer Institute Cancer Therapy Evaluation Program. RESULTS: Trial availability and accrual improved more quickly at NCCCP sites compared with national trends. Phase III trial availability increased 8% nationally versus 16% across NCCCP sites, and accrual increased 30% nationally versus 133% across NCCCP sites. Accrual of racial and ethnic minorities rose 82%, from 83 to 151 patients, and accrual of patients age ≥ 65 years rose by 221%, from 200 to 641 patients. Change in trial portfolio and accrual differed by sophistication of the site and by prior experience in conducting clinical trials at the site. CONCLUSION: Despite the short duration, the NCCCP pilot resulted in an increase in the number of open trials as well as patient accrual at a faster rate than that observed nationally. These results, coupled with insights into the relative success of sites with varying sophistication at the outset, provide promise that lessons learned can be applied more broadly to increase research participation.

Response Rate as a Regulatory End Point in Single-Arm Studies of Advanced Solid Tumors.

IMPORTANCE: Objective response rate (ORR) is an increasingly important end point for accelerated development of highly active anticancer therapies, yet its relationship to regulatory approval is not well characterized. OBJECTIVE: To identify circumstances in which a high ORR is associated with regulatory approval, and therefore might be an appropriate end point for definitive single-arm studies of anticancer therapies. DATA SOURCE: A database of all oncology clinical trials registered at clinicaltrials.gov between October 1, 2007, and September 30, 2010. STUDY SELECTION: Trials of palliative systemic therapies for 4 measurable solid tumor types, limited to those with trial arms of at least 20 patients reporting ORR per Response Evaluation Criteria in Solid Tumors (RECIST). DATA EXTRACTION AND SYNTHESIS: A systematic search was used to identify the reported ORR for each eligible treatment arm that had been presented publicly. MAIN OUTCOMES AND MEASURES: For each treatment regimen, defined as a single-agent or unique combination of agents for 1 cancer type, the mean ORR and the maximum ORR statistically exceeded were calculated, and their association with regulatory approval was studied. A regimen was considered approved for a specific cancer type if it had received regulatory approval in any country for treatment of advanced cancer of that type. RESULTS: From 1800 trials, 874 eligible trial arms in 578 eligible trials were identified; 542 arms had ORR data available for 294 regimens. Maximum ORR and mean ORR were significantly associated with regulatory approval (τ = 0.27, P < .001; τ = 0.12, P = .01); this relationship was stronger for single-agent therapies (τ = 0.49; τ = 0.41) than for combination regimens (τ = 0.28; τ = 0.17). Evaluation of ORR thresholds between 20% and 60% as potential trial end points demonstrated that ORR statistically exceeding 30% with a single agent had 98% specificity and 89% positive predictive value for identifying regimens achieving regulatory approval. CONCLUSIONS AND RELEVANCE: For single-agent regimens, high ORR was associated with regulatory approval; this relationship was less strong for combination regimens. Our data suggest that high ORR (eg, statistically exceeding an ORR of 30%) is an appropriate end point for single-arm trials aiming to demonstrate breakthrough activity of a single-agent anticancer therapy.

Sequential Therapy in Metastatic Renal Cell Carcinoma.

The treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically in the past decade. As the number of available agents, and related volume of research, has grown, it is increasingly complex to know how to optimally treat patients. The authors are practicing medical oncologists at the US Oncology Network, the largest community-based network of oncology providers in the country, and represent the leadership of the Network's Genitourinary Research Committee. We outline our thought process in approaching sequential therapy of mRCC and the use of real-world data to inform our approach. We also highlight the evolving literature that will impact practicing oncologists in the near future.

Deferred systemic therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: With the advent of small-molecule "targeted" therapies, the prevailing treatment paradigm for metastatic renal cell carcinoma (mRCC) is that all patients who are able to tolerate systemic therapy should receive it. However, oncologists often defer the initiation of systemic therapy for patients with mRCC. The outcomes of and clinical reasoning behind the initial management of patients with mRCC without systemic therapy have not been well described. METHODS: We conducted a retrospective cohort study of all patients with mRCC treated within the Duke University Health System and diagnosed from January 1, 2007, to January 1, 2011. We defined our cohort as patients who did not receive systemic therapy during the first year after mRCC diagnosis. The clinical rationale for the lack of immediate treatment was ascertained by manual chart review. RESULTS: A total of 60 of 268 patients (22%) with mRCC managed without initial systemic therapy were included in our study. The median age was 61.2 years, the median duration from diagnosis of localized RCC to development of mRCC was 41.9 months, and 91% of patients had Eastern Cooperative Oncology Group functional status of ≤ 1. Of the patients, 60% were managed with surgical metastasectomy alone, 12% received multiple local treatment modalities, 13% received active surveillance, 7% were managed supportively, and 8% were categorized as "other." CONCLUSIONS: The majority of patients in our cohort had favorable disease characteristics and experienced favorable outcomes with surgery alone. Our results suggest that this population could represent 20% of patients with mRCC in tertiary care settings. Prospective data are needed to evaluate deferred systemic therapy as a management strategy.

Clinical Trial Participants With Metastatic Renal Cell Carcinoma Differ From Patients Treated in Real-World Practice.

PURPOSE: Although narrow eligibility criteria improve the internal validity of clinical trials, they may result in differences between study populations and real-world patients, threatening generalizability. Therefore, we evaluated whether patients treated for metastatic renal cell cancer (mRCC) in routine clinical practice are similar to those enrolled onto clinical trials. PATIENTS AND METHODS: In this cohort study, we compared baseline characteristics of patients with mRCC in phase III clinical trials of new targeted therapies and those in a retrospective registry composed of academic (Duke) and community (ACORN Network) practices. RESULTS: A total of 438 registry patients received sunitinib, sorafenib, temsirolimus, or pazopanib (most commonly used agents) in first-line treatment. Registry patients receiving tyrosine kinase inhibitors (sunitinib, sorafenib, or pazopanib) were more likely to have poor-risk disease by Memorial Sloan Kettering Cancer Center criteria (poor, 7.4% v 2.9%; P < .001; favorable, 30.1% v 43.8%; P < .001) and to have impaired performance status (Eastern Cooperative Oncology Group > 1, 11.1% v 0.6%; P < .001). However, registry patients receiving temsirolimus were less likely to have poor-risk disease (poor, 10.2% v 69.4%; P < .001; favorable, 16.9% v 0%; P < .001). Thus, 39.0% of registry patients would have been excluded from the phase III clinical trial testing the drug they received. CONCLUSION: Patients with mRCC treated with tyrosine kinase inhibitors in real-world clinical practice are sicker than those enrolled onto pivotal clinical trials, and more than one third are trial ineligible. Application of clinical trial findings to dissimilar populations may result in patient harm. Clinical research with more inclusive eligibility criteria is needed to appropriately guide real-world practice.

Initial Trends in the Use of the 21-Gene Recurrence Score Assay for Patients With Breast Cancer in the Medicare Population, 2005-2009.

IMPORTANCE: In 2006, the Centers for Medicare & Medicaid Services approved coverage for the use of the 21-gene recurrence score (RS) assay in women with early-stage, estrogen receptor-positive, node-negative breast cancers to help guide recommendations for adjuvant chemotherapy. Use of the assay in community settings has not been previously examined in a nationally representative sample of patients. OBJECTIVE: To examine trends in the use of the RS assay in routine clinical practice in a nationally representative sample of women with breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Retrospective observational study of Medicare beneficiaries diagnosed with incident breast cancer between 2005 and 2009, as recorded in a Surveillance, Epidemiology, and End Results data set with linked Medicare claims through 2010. MAIN OUTCOMES AND MEASURES: Demographic and clinical variables associated with the use of the assay. RESULTS: A total of 70,802 patients met the study criteria. Use of the RS assay increased from 1.1% in 2005 to 10.1% in 2009 (P < .001). The majority of tests (60.9%) occurred in patients with National Comprehensive Cancer Network-defined intermediate-risk disease (ie, estrogen receptor-positive, node-negative tumors >1 cm). Most patients with other than intermediate-risk disease had borderline indications for testing, including T1b (47.5%) or N1 (26.8%) disease. Testing was associated with younger age, fewer comorbid conditions, higher-grade disease, and being married. Among patients younger than 70 years with intermediate-risk disease, testing rates increased from 7.7% in 2005 to 38.8% in 2009 (P < .001). In multivariable analysis, testing was modestly higher in Northeast than in Western registries (odds ratio, 1.83; 95% CI, 1.49-2.26) but was otherwise not associated with region, local census tract demographic characteristics, black race, location in an urban area, or tumor histologic characteristics. CONCLUSIONS AND RELEVANCE: The RS assay was adopted quickly in clinical practice after the Medicare coverage decision in 2006, and use appears to be consistent with guidelines and equitable across geographic and racial groups. Factors influencing adoption of the assay and its impact on adjuvant chemotherapy use in clinical practice remain important areas of study.

Relationship Between Cancer and Cardiovascular Outcomes Following Percutaneous Coronary Intervention.

BACKGROUND: Cardiovascular disease and cancer increasingly coexist, yet relationships between cancer and long-term cardiovascular outcomes post-percutaneous coronary intervention (PCI) are not well studied. METHODS AND RESULTS: We examined stented PCI patients at Duke (1996-2010) using linked data from the Duke Information Systems for Cardiovascular Care and the Duke Tumor Registry (a cancer treatment registry). Our primary outcome was cardiovascular mortality. Secondary outcomes included composite cardiovascular mortality, myocardial infarction, or repeat revascularization and all-cause mortality. We used adjusted cause-specific hazard models to examine outcomes among cancer patients (cancer treatment pre-PCI) versus controls (no cancer treatment pre-PCI). Cardiovascular mortality was explored in a cancer subgroup with recent (within 1 year pre-PCI) cancer and in post-PCI cancer patients using post-PCI cancer as a time-dependent variable. Among 15 008 patients, 3.3% (n=496) were cancer patients. Observed rates of 14-year cardiovascular mortality (31.4% versus 27.7%, P=0.31) and composite cardiovascular death, myocardial infarction, or revascularization (51.1% versus 55.8%, P=0.37) were similar for cancer versus control groups; all-cause mortality rates were higher (79.7% versus 49.3%, P<0.01). Adjusted risk of cardiovascular mortality was similar for cancer patients versus controls (hazard ratio 0.95; 95% CI 0.76 to 1.20) and for patients with versus without recent cancer (hazard ratio 1.46; 95% CI 0.92 to 2.33). Post-PCI cancer, present in 4.3% (n=647) of patients, was associated with cardiovascular mortality (adjusted hazard ratio 1.51; 95% CI 1.11 to 2.03). CONCLUSIONS: Cancer history was present in a minority of PCI patients but was not associated with worse long-term cardiovascular outcomes. Further investigation into PCI outcomes in this population is warranted.

Biosimilars: a cure to the U.S. health care cost conundrum?

As the cost of healthcare continues to rise and patents on biologics near expiration, biosimilars are gaining visibility as a mechanism for cost reduction. Yet, the introduction of biosimilars into the U.S. market will be complex, due to the related complexity of production, research requirements, and regulatory uncertainty. The purpose of this paper is to frame the relevant issues in order to provide context for stakeholders. It is particularly crucial that clinicians understand the scientific, regulatory, legislative and economic considerations involved in order to ensure that the path to approval is consistent with their needs and that appropriate utilization occurs, once approved.

Comparative effectiveness research: moving medical oncology forward.

Comparative effectiveness research (CER) is critically needed in medical oncology to improve the care being delivered to oncology patients. As medical oncologists are forced to rely on insufficient data as a part of daily treatment decision making, and as the cancer treatment landscape evolves quickly relative to other areas of medicine, CER is particularly pressing in our field. Continued reliance on randomized clinical trials is a part of the solution, but it cannot be the sole answer. As new and richer data sources become available addressing quality of life, resource utilization, and other critical elements, the implementation of CER will advance. Its true power will lie in linkages to "learning health systems" and real-time application to the day-to-day practice of medicine.

The impact of specialty pharmaceuticals as drivers of health care costs.

The pharmaceutical industry is shifting its focus from blockbuster small molecules to specialty pharmaceuticals. Specialty pharmaceuticals are novel drugs and biologic agents that require special handling and ongoing monitoring, are administered by injection or infusion, and are sold in the marketplace by a small number of distributors. They are frequently identified by having a cost to payers and patients of $600 or more per treatment. The total costs of the new agents are likely to have a substantial impact on overall health care costs and on patients during the next decade, unless steps are taken to align competing interests. We examine the economic and policy issues related to specialty pharmaceuticals, taking care to consider the impact on patients. We assess the role of cost-sharing provisions, legislation that is promoting realignment within the market, the role of biosimilars in price competition, and the potential for novel drug development paradigms to help bend the cost curve. The economic aspects of this analysis highlight the need for a far-reaching discussion of potential novel approaches to innovation pathways in our quest for both affordability and new technology.