Real-World Conundrums and Biases in the Use of White Cell Growth Factors.

We present the 2015 American Society of Clinical Oncology (ASCO) white cell growth factors, or colony-stimulating factor (CSF), guidelines, updated from 2006. One new indication has been added-dose-intense chemotherapy for bladder cancer-to accompany the existing use for dose-dense breast cancer chemotherapy. Colony-stimulating factors remain appropriate for any regimen where the risk of febrile neutropenia is about 20% per cycle and dose reduction is not appropriate. Based on new evidence from multiple trials, CSF use is no longer indicated in treatment of lymphoma unless there are special risk factors. The United States accounts for 78% of the sales of CSF. The panel approved the use of all biosimilars, but the cost savings will be small as the price is about 80% of the branded CSFs. More biosimilars at lower cost are awaited. Methods to reduce use without harm to patients, by requiring justification according to accepted guidelines, are ongoing.

Baseline Estimates of Adherence to American Society of Clinical Oncology/American Board of Internal Medicine Choosing Wisely Initiative Among Patients With Cancer Enrolled With a Large Regional Commercial Health Insurer.

PURPOSE: The American Society of Clinical Oncology (ASCO)/American Board of Internal Medicine (ABIM) Choosing Wisely (CW) measures aim to reduce the use of interventions that lack evidence of benefit in cancer care. The study presented here characterized adherence to the 2012 ASCO/ABIM CW recommendations by linking health plan claims data with a regional cancer registry and sought to identify areas for research interventions to improve adherence. METHODS: SEER records for patients diagnosed with cancer in Western Washington State between 2007 and 2014 were linked with enrollment and claims from a large regional commercial insurance plan. Using claims and SEER records, algorithms were developed to characterize adherence to each CW measure. In addition, we calculated differences in total reimbursements and procedure-specific reimbursements for patients receiving adherent and nonadherent care. RESULTS: A total of 22,359 unique individuals with cancer were linked with insurance enrollment records and met basic eligibility criteria. Overall adherence varied from 53% (breast surveillance) to 78% (breast staging). Within each measure, adherence varied substantially by stage at diagnosis and by cancer site in situations in which the CW measure affected multiple types of cancer. The difference in reimbursements between adherent and nonadherent populations across all five measures was approximately $29 million. CONCLUSION: Adherence to the ASCO/ABIM CW measures varies widely, as does the cost implication of nonadherence. A structured approach to evaluating adherence and cost impact is needed before developing programs aimed at improving adherence to the ASCO/ABIM CW measures.

Uptake and economic impact of first-cycle colony-stimulating factor use during adjuvant treatment of breast cancer.

PURPOSE: In 2002, pegfilgrastim was approved by the US Food and Drug Administration and the benefits of dose-dense breast cancer chemotherapy, especially for hormone receptor (HR) -negative tumors, were reported. We examined first-cycle colony-stimulating factor use (FC-CSF) before and after 2002 and estimated US expenditures for dose-dense chemotherapy. METHODS: We identified patients in Surveillance, Epidemiology, and End Results-Medicare greater than 65 years old with stages I to III breast cancer who had greater than one chemotherapy claim within 6 months of diagnosis(1998 to 2005) and classified patients with an average cycle length less than 21 days as having received dose-dense chemotherapy. The associations of patient, tumor, and physician-related factors with the receipt of any colony-stimulating factor (CSF) and FC-CSF use were analyzed by using generalized estimating equations. CSF costs were estimated for patients who were undergoing dose-dense chemotherapy. RESULTS: Among the 10,773 patients identified, 5,266 patients (48.9%) had a CSF claim. CSF use was stable between 1998 and 2002 and increased from 36.8% to 73.7% between 2002 and 2005, FC-CSF use increased from 13.2% to 67.9%, and pegfilgrastim use increased from 4.1% to 83.6%. In a multivariable analysis, CSF use was associated with age and chemotherapy type and negatively associated with black/Hispanic race, rural residence, and shorter chemotherapy duration. FC-CSF use was associated with high socioeconomic status but not with age or race/ethnicity. The US annual CSF expenditure for women with HR-positive tumors treated with dose-dense chemotherapy is estimated to be $38.8 million. CONCLUSION: A rapid increase in FC-CSF use occurred over a short period of time, which was likely a result of the reported benefits of dose-dense chemotherapy and the ease of pegfilgrastim administration. Because of the increasing evidence that elderly HR-positive patients do not benefit from dose-dense chemotherapy, limiting pegfilgrastim use would combat the increasing costs of cancer care.

Use of colony-stimulating factors with chemotherapy: opportunities for cost savings and improved outcomes.

Myeloid colony-stimulating factors (CSFs) decrease the risk of febrile neutropenia (FN) from high-risk chemotherapy regimens administered to patients at 20% or greater risk of FN, but little is known about their use in clinical practice. We evaluated CSF use in a multiregional population-based cohort of lung and colorectal cancer patients (N = 1849). Only 17% (95% confidence interval [CI] = 8% to 26%) patients treated with high-risk chemotherapy regimens received CSFs, compared with 18% (95% CI = 16% to 20%) and 10% (95% CI = 8% to 12%) of patients treated with intermediate- (10%-20% risk of FN) and low-risk (<10% risk of FN) chemotherapy regimens, respectively. Using a generalized estimating equation model, we found that enrollment in a health maintenance organization (HMO) was strongly associated with a lower adjusted odds of discretionary CSF use, compared with non-HMO patients (odds ratio = 0.44, 95% CI = 0.32 to 0.60, P < .001). All statistical tests were two-sided. Overall, 96% (95% CI = 93% to 98%) of CSFs were administered in scenarios where CSF therapy is not recommended by evidence-based guidelines. This finding suggests that policies to decrease CSF use in patients at lower or intermediate risk of FN may yield substantial cost savings without compromising patient outcomes.

Economic analysis of prophylactic pegfilgrastim in adult cancer patients receiving chemotherapy.

OBJECTIVES: Neutropenia and its complications, including febrile neutropenia (FN), are a common side effect of cancer chemotherapy. Results of clinical trials showed that prophylactic use of granulocyte colony-stimulating factors (G-CSF) is effective in preventing FN. In this study, the cost effectiveness (measured as cost per quality-adjusted time [days]) of three treatment alternatives were evaluated: no G-CSF, filgrastim administered daily for 7-12 days after chemotherapy, and a pegylated form of G-CSF pegfilgrastim, administered once per cycle. METHODS: A cost-utility model based on standard clinical practice of treating FN with immediate hospitalization or with ambulatory treatment, from a societal perspective was developed. Direct medical cost estimates for hospitalization were derived from claims data reported by 115 US academic medical centers. Indirect medical costs, productivity costs, probabilities, and utilities are based on published literature. Results were subjected to sensitivity analyses and 95% confidence intervals are based on a Monte Carlo simulation. RESULTS: Mean estimated costs/day of hospitalization were $1984 (SD $1040, N = 24,687) for surviving patients and $3139 (SD $2014, N = 1437) for dying patients. Under baseline conditions, pegfilgrastim dominated both filgrastim and no G-CSF, with expected costs and effectiveness of $4203 and 12.361 quality adjusted life-days (QALDs) for no G-CSF, $3058 and 12.967 QALDs for pegfilgrastim, and $5264 and 12.698 QALDs for filgrastim. CONCLUSIONS: This cost-utility analysis provides strong evidence that pegfilgrastim is not only cost-effective but also cost-saving in most common clinical and economic settings. There appear to be both clinical and economic benefits from prophylactic administration of pegfilgrastim.

Review of the value of colony stimulating factors for prophylaxis of febrile neutropenic episodes in adult patients treated for haematological malignancies.

Chemotherapy-induced neutropenia is a major dose-limiting toxicity of systemic cancer chemotherapy that can lead to fever and infection, requiring prompt analysis and in-patient treatment with broad-spectrum antibiotics. Complicated neutropenia may lead to reduction and/or delay of systemic anti-cancer treatment, which may compromise outcome. Haematopoietic growth factors have the ability to augment haematopoietic cell cycling and are used to facilitate more dose-intense treatments and to decrease treatment-related complications. This review focuses on randomised trials that investigated the use of colony-stimulating factors (CSF) to prevent treatment-related febrile complications in haematological malignancies in (younger) adult patients. In general, these studies demonstrated that CSF reduced the duration of severe neutropenia but not always its febrile complications; therefore inconsistent results regarding clinically relevant reduction of hospitalisation, duration of therapeutic antibiotics, infection-related or disease-related mortality and economic effects were reported. Current developments in treatment of haematological malignancies will pose new challenges as a shift in infectious pathogens can be expected.

Colony-stimulating factors in the management of neutropenia and its complications.

Granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF are potent drugs used to increase neutrophil counts after myelosuppressive chemotherapy. However, in various indications, the use of CSFs has no clinical benefit with regard to morbidity or mortality from infectious complications, frequency of antibiotic use, or rate of hospitalization. Thus, the application of CSFs should be limited to indications with proven clinical benefits or evidence of cost-effectiveness. This review will provide an overview of the state-of-the-art use of CSFs in chemotherapy-associated neutropenia, transplantation, and bone marrow failure syndromes. In addition, recently developed drugs for accelerated hematopoietic recovery will be presented.

Guidelines of the National Comprehensive Cancer Network on the use of myeloid growth factors with cancer chemotherapy: a review of the evidence.

The prophylactic use of myeloid growth factors reduces the risk of chemotherapy-induced neutropenia and its complications, including febrile neutropenia and infection-related mortality. Perhaps most importantly, the prophylactic use of colony-stimulating factors (CSFs) has been shown to reduce the need for chemotherapy dose reductions and delays that may limit chemotherapy dose intensity, thereby increasing the potential for prolonged disease-free and overall survival in the curative setting. National surveys have shown that the majority of patients with potentially curable breast cancer or non-Hodgkin's lymphoma (NHL) do not receive prophylactic CSF support. In this issue, the National Comprehensive Cancer Network presents guidelines for the use of myeloid growth factors in patients with cancer. These guidelines recommend a balanced clinical evaluation of the potential benefits and harms associated with chemotherapy to define the treatment intention, followed by a careful assessment of the individual patient's risk for febrile neutropenia and its complications. The decision to use prophylactic CSFs is then based on the patient's risk and potential benefit from such treatment. The routine prophylactic use of CSFs in patients receiving systemic chemotherapy is recommended in patients at high risk (>20%) of developing febrile neutropenia or related complications that may compromise treatment. Where compelling clinical indications are absent, the potential for CSF prophylaxis to reduce or offset costs by preventing hospitalization for FN should be considered. The clinical, economic, and quality of life data in support of these recommendations are reviewed, and important areas of ongoing research are highlighted.

Effect of outpatient treatment of febrile neutropenia on the risk threshold for the use of CSF in patients with cancer treated with chemotherapy.

OBJECTIVES: Febrile neutropenia (FN) in patients with cancer treated with chemotherapy has traditionally been managed with inpatient broad-spectrum antibiotics until the infection and neutropenia have resolved. A newer strategy is outpatient oral or intravenous antibiotics in selected patients after an initial hospitalization. We sought to determine these costs, both overall and relative to those of traditional management, and the optimal role of prophylactic colony-stimulating factor (CSF) in patients at greatest risk for FN. METHODS: Existing economic decision models were modified by incorporating a treatment strategy for FN in which patients are classified as high- and low-risk according to criteria described by Talcott. Low-risk patients were assumed to be treated as outpatients. Overall costs with the revised economic model were assessed and sensitivity analyses were performed. RESULTS: The costs of an episode of FN were estimated as 1) no CSF: dollar 13,355; 2) CSF with hospitalization for FN: dollar 8677; and 3) CSF with risk stratification and outpatient management in low-risk patients: dollar 8188. The risk threshold for the cost-effective use of CSF was only slightly lower with outpatient treatment. When all patients with FN are treated as inpatients and the cost of hospitalization is dollar 1750/day the risk threshold for FN at which prophylactic CSF becomes cost-effective is 16%. It is 15% when low-risk patients are treated as outpatients. CONCLUSIONS: Outpatient treatment slightly decreases the risk threshold for FN at which prophylactic CSF becomes cost-effective. The limited economic effect of this strategy may be because the patients who were at greatest risk of complications had significantly longer lengths of stay and accounted for most of the hospitalization costs.

The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia.

Healthcare costs continue to rise with hospitalization representing the single largest component of direct medical costs associated with cancer care. Neutropenia and its complications including febrile neutropenia remain the major dose-limiting toxicity associated with systemic cancer chemotherapy. Febrile neutropenia often occurs early in the course of chemotherapy and is associated with substantial morbidity, mortality and cost. The colony-stimulating factors (CSFs) have been used effectively in a variety of clinical settings to prevent or treat febrile neutropenia and to assist patients receiving dose-intensive chemotherapy. A meta-analysis of the available randomized controlled trials (RCTs) has confirmed the efficacy of prophylactic CSFs. Economic models based on measures of resource utilization derived from RCTs have provided estimates of expected treatment costs along with febrile neutropenia risk threshold estimates for the cost saving use of the CSFs. Recent studies have demonstrated the potential value of targeting the CSFs toward patients at greatest risk based on accurate and valid predictive models.

Effects of indirect and additional direct costs on the risk threshold for prophylaxis with colony-stimulating factors in patients at risk for severe neutropenia from cancer chemotherapy.

STUDY OBJECTIVES: Previous studies have used direct hospital costs to determine the threshold at which the cost of prophylactic use of colony-stimulating factor (CSF) is offset by savings from the lower risk of hospitalization for febrile neutropenia. By conducting a survey of patients in whom febrile neutropenia had developed during treatment with chemotherapy, we sought to reassess these costs by including estimates of indirect costs associated with febrile neutropenia as well as new categories of direct costs that were not previously available. Costs were included in an existing cost-minimization model, and their effect on the risk threshold at which the prophylactic use of CSF becomes cost saving was determined. PATIENTS: A sample survey of 26 patients with ovarian cancer who were treated with chemotherapy and developed febrile neutropenia. INTERVENTION: Analysis of data from patients' questionnaires containing survey items on indirect costs and additional direct costs associated with febrile neutropenia. MEASUREMENTS AND MAIN RESULTS: Estimates of indirect costs and other direct costs from the questionnaires were included in an existing cost-minimization model, and risk thresholds were recalculated. Before modification, the model showed cost neutrality for prophylactic use of CSF when the risk of hospitalization for febrile neutropenia was approximately 23%. Including previously excluded direct costs and indirect costs ranging from 1000-5000 dollars attributable to severe neutropenia in the model lowered the risk threshold for hospitalization for febrile neutropenia at which the prophylactic use of CSF becomes cost neutral to between 22% and 18%. CONCLUSION: Including additional direct as well as indirect costs associated with chemotherapy-induced neutropenia permits a more realistic assessment of the possible effect of prophylactic use of CSF from a societal perspective. Despite the limited size of the survey, this study shows a cost-benefit rationale to support prophylactic use of CSF in a greater proportion of patients treated with chemotherapy.

Risk assessment in oncology clinical practice. From risk factors to risk models.

Myelosuppression and neutropenia represent the major dose-limiting toxicity of cancer chemotherapy. Chemotherapy-induced neutropenia may be accompanied by fever, presumably due to life-threatening infection, which generally requires hospitalization for evaluation and treatment with empiric broad-spectrum antibiotics. The resulting febrile neutropenia is a major cause of the morbidity, mortality, and costs associated with the treatment of patients with cancer. Furthermore, the threat of febrile neutropenia often results in chemotherapy dose reductions and delays, which can compromise long-term clinical outcomes. Prophylactic colony-stimulating factor (CSF) has been shown to reduce the incidence, severity, and duration of neutropenia and its complications. Guidelines from the American Society of Clinical Oncology recommend the use of CSF on the basis of the myelosuppressive potential of the chemotherapy regimen. The challenge in ensuring the appropriate and cost-effective use of prophylactic CSF is to determine which patients would be most likely to benefit from it. A number of patient-, disease-, and treatment-related factors are associated with an increased risk of neutropenia and its complications. A number of clinical predictive models have been developed from retrospective datasets to identify patients at greater risk for neutropenia and its complications. Early studies have demonstrated the potential of such models to guide the targeted use of CSF to those patients who are most likely to benefit from the early use of these supportive agents. Additional prospective research is needed to develop more accurate and valid risk models and to evaluate the efficacy and cost-effectiveness of model-targeted use of CSF in high-risk patients.

Evidence-based use of colony-stimulating factors in elderly cancer patients.

BACKGROUND: Neutropenia and its complications represent the major dose-limiting toxicity of cancer chemotherapy, especially in the elderly. Hematopoietic growth factors have been shown to reduce the severity and duration of febrile neutropenia (FN) and to sustain chemotherapy dose intensity. METHODS: A systematic review was undertaken of studies of the relationship between age and the risk of neutropenia and its complications. Recent studies of the "Awareness of Neutropenia in Chemotherapy Study Group" related to the impact of age on neutropenic complications are also summarized. RESULTS: The risk of FN associated with standard regimens increases with age and appears to be greatest during the first cycle of chemotherapy. FN continues to have a considerable clinical, economic, and quality-of-life impact on affected individuals. The risk of mortality associated with hospitalization with FN also increases with age but is largely associated with the higher rate of comorbidities observed in the elderly population. Despite increasing evidence that elderly patients experience similar benefit from cancer chemotherapy, reductions in dose intensity often compromise response rates and long-term survival. The hematopoietic growth factors reduce the risk of neutropenic events and the need for reduced dose intensity in elderly cancer patients. Primary prophylaxis with colony-stimulating factors (CSFs) reduces the risk of FN and its complications in elderly patients receiving moderately intensive systemic chemotherapy for responsive malignancies. CSFs also appear to reduce cost and improve quality of life in selected elderly patients receiving chemotherapy. CONCLUSIONS: Primary prophylaxis with CSFs should be considered in elderly patients with responsive and potentially curable malignancies who receive moderately intensive chemotherapy.