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Gary H. Lyman

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.

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Gary H. Lyman

Chemotherapy dose intensity represents unit dose of chemotherapy administered per unit time. Dose intensity can be increased or decreased through altering dose administered, time interval of administration, or both. Evidence supporting the importance of delivered chemotherapy dose intensity on clinical outcomes in patients with potentially curable malignancies comes from in vitro studies of cancer cell lines and abundant in vivo preclinical studies, in addition to retrospective and prospective clinical trials in both advanced and early-stage disease settings. Myelosuppression continues to represent the major dose-limiting toxicity of cancer chemotherapy, resulting in considerable morbidity and mortality along with frequent reductions in chemotherapy dose intensity, which may compromise disease control and survival. Several retrospective and prospective randomized trials have shown that reductions in the chemotherapy dose intensity established in efficacy studies may compromise long-term disease control and survival. Despite compelling data, surveys in the United States and elsewhere have reported that dose reductions and delays frequently occur in clinical practice, even in the potentially curative setting. Alternatively, an increase in dose intensity above standard may be achieved through either increasing the dose of individual agents (dose escalation) or compressing or shortening the treatment interval (dose-dense). In early studies, dose-dense schedules showed an increase in survival, whereas the benefit of dose escalation studies has been less consistent and may be accompanied by other dose-limiting toxicities. This article focuses on the rationale for delivering full chemotherapy dose intensity, the apparent reasons for failing to deliver optimal treatment, and available strategies for sustaining full chemotherapy dose intensity when indicated. The delivery of full chemotherapy dose intensity in patients with potentially curable malignancies should be considered a quality of care indicator in clinical oncology.

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Gary H. Lyman

Biosimilars are here to stay, but whether they will enjoy widespread uptake remains to be seen. The FDA sets a high bar for approval of biosimilar products, yet many clinicians remain skeptical about the efficacy and safety of these agents. Favorable experience with >30 biosimilars in Europe provides some reassurance that these agents are safe and effective and can be substituted for the reference product.

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Bradford R. Hirsch and Gary H. Lyman

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.

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Gary H. Lyman and Marek S. Poniewierski

Neutropenia and its complications, including febrile neutropenia (FN), represent major toxicities associated with cancer chemotherapy, resulting in considerable morbidity, mortality, and costs. The myeloid growth factors such as granulocyte colony-stimulating factor (G-CSF) have been shown to reduce the risk of neutropenia complications while enabling safe and effective chemotherapy dose intensity. Concerns about the high costs of these agents along with limited physician adherence to clinical practice guidelines, resulting in both overuse and underuse, has stimulated interest in models for individual patient risk assessment to guide appropriate use of G-CSF. In a model developed and validated by the ANC Study Group, half of patients were classified as high risk and half as low risk based on patient-, disease-, and treatment-related factors. This model has been further validated in an independent patient population. Physician-assessed risk of FN, as well as the decision to use prophylactic CSF, has been shown to correlate poorly with the FN risk estimated by the model. Additional modeling efforts in both adults and children receiving cancer treatment have been reported. Identification of patients at a high individual risk for FN and its consequences may offer the potential for optimal chemotherapy delivery and patient outcomes. Likewise, identification of patients at low risk for neutropenic events may reduce costs when such supportive care is not warranted. This article reviews and summarizes FN modeling studies and the opportunities for personalizing supportive care in patients receiving chemotherapy.

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Bradford R. Hirsch and Gary H. Lyman

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.

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Gary H. Lyman and David C. Dale

Myeloid growth factors are used to reduce myelotoxicity and the risk of infection after cancer chemotherapy and in patients with chronic neutropenia. This article addresses the long-term benefits and risks associated with granulocyte colony-stimulating factor (G-CSF) therapy in both settings. A systematic review of randomized controlled trials recently reported long-term outcomes regarding the risk of second malignancies and overall survival. Based on these studies, the risk for acute myeloid leukemia (AML) associated with known carcinogenic agents, such as chemotherapy, could not be distinguished from any risk associated with growth factor support. However, the enhanced delivery of chemotherapy dose intensity enabled by the use of G-CSF in these studies was associated with a significant reduction in all-cause mortality. Although some reduction in treatment-related mortality with G-CSF support may occur, the observed improvement in long-term survival likely relates to better disease control with more-intense G-CSF–supported chemotherapy. Myeloid growth factors have also been shown to benefit patients with severe chronic neutropenia. Almost all patients with cyclic, congenital, or idiopathic neutropenia experience response to G-CSFs. Treatment is titrated to determine a dose that provides a safe elevation in neutrophil counts. Reports have shown that patients can be maintained for years at the same dose after adjusting for growth and development. In congenital neutropenia, the inherent risk of developing myelodysplastic syndromes or AML requires careful monitoring, including routine blood counts and annual bone marrow examinations.

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Gary H. Lyman and Jessica Malone Kleiner

Three different practice guidelines for the myeloid growth factors were recently published by major professional organizations. A comprehensive review and comparison of the guidelines using a priori structured content criteria and a previously validated quality appraisal tool are reported. The final recommendations from these guidelines are consistent for primary prophylaxis with the colony-stimulating factors (CSFs) when the risk of febrile neutropenia is in the range of 20% or greater. All 3 guidelines also recommend prophylactic use of myeloid growth factors in patients with important factors increasing individual risk of neutropenic complications. The recommendation that patients receiving regimens associated with lower risk should have CSF use guided by individual risk assessment is also consistent. Critical quality appraisal indicates that the scope, purpose, stakeholder involvement, and applicability of these guidelines differ little. The American Society of Clinical Oncology and European Organization for Research and Treatment of Cancer guidelines place more emphasis on comprehensive literature reviews, and the National Comprehensive Cancer Network guidelines are more current based on systematic annual updates. Presentation clarity also favors National Comprehensive Cancer Network guidelines, with recommendations generally presented as both text and algorithmic diagram.

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Michaela A. Dinan, Bradford R. Hirsch and Gary H. Lyman

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.

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David C. Dale, Gordon C. McCarter, Jeffrey Crawford and Gary H. Lyman

Delivery of cancer chemotherapy is often limited by myelotoxicity, primarily neutropenia. As part of an effort to create a model to predict the risk of chemotherapy-induced neutropenia, we reviewed the reports of randomized clinical trials with more than 50 patients per arm in early-stage breast cancer (ESBC) and non-Hodgkin's lymphoma (NHL) published between 1990 and 2000. We observed that no hematologic toxicity data were reported in 39% and 34% of the ESBC and NHL trials, respectively. The remaining trials reported on hematologic toxicity in 16 different ways. When reported, rates of neutropenia, leukopenia, and hematotoxicity varied widely with the same and similar chemotherapy regimens. Dose-intensity data were not reported in 39% and 54% of ESBC and NHL trials, respectively. The majority of the remaining studies reported incomplete dose-intensity data such as percentages of patients completing all cycles or receiving a given percentage of planned dose intensity. Only 28% reported the mean or median relative dose intensity received by patients. Based on this review, we conclude that current practices for reporting chemotherapy treatments are inadequate for describing the risk of chemotherapy to patients or for quantitatively assessing the risk of treatment alternatives. We recommend that standard procedures for documenting and reporting hematologic toxicity and dose intensity in cancer chemotherapy trials be required for publication of chemotherapy trials.