Neutrophils are the body's critical phagocytic cells for defense against bacterial and fungal infections; bone marrow must produce approximately 10 x 109 neutrophils/kg/d to maintain normal blood neutrophil counts. Production of neutrophils depends on myeloid growth factors, particularly granulocyte colony-stimulating factor (G-CSF). After the original phase of development, researchers modified these growth factors to increase their size and delay renal clearance, increase their biologic potency, and create unique molecules for business purposes. Pegylated G-CSF is a successful product of these efforts. Researchers have also tried to identify small molecules to serve as oral agents that mimic the parent molecules, but these programs have been less successful. In 2006, the European Medicines Agency established guidelines for the introduction of new biologic medicinal products claimed to be similar to reference products that had previously been granted marketing authorization in the European community, called bio-similars. Globally, new and copied versions of G-CSF and other myeloid growth factors are now appearing. Some properties of the myeloid growth factors are similar to other agents, offering opportunities for the development of alternative drugs and treatments. For example, recent research shows that hematopoietic progenitor cells can be mobilized with a chemokine receptor antagonist, chemotherapy, G-CSF, and granulocyte macrophage colony-stimulating factor. Advances in neutrophil biology coupled with better understanding and development of myeloid growth factors offer great promise for improving the care of patients with cancer and many other disorders.
Neutrophil Biology and the Next Generation of Myeloid Growth Factors
David C. Dale
Long-Term Outcomes of Myeloid Growth Factor Treatment
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.
Myelotoxicity and Dose Intensity of Chemotherapy: Reporting Practices From Randomized Clinical Trials
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.
Risk and Timing of Neutropenic Events in Adult Cancer Patients Receiving Chemotherapy: The Results of a Prospective Nationwide Study of Oncology Practice
Jeffrey Crawford, David C. Dale, Nicole M. Kuderer, Eva Culakova, Marek S. Poniewierski, Debra Wolff, and Gary H. Lyman
This study was undertaken to describe the relationship between the occurrence and timing of neutropenic events and chemotherapy treatment in a community-based population of patients with cancer. The study included 2962 patients with breast, lung, colorectal, lymphoma, and ovarian cancers from a prospective U.S. registry of patients initiating a new chemotherapy regimen. Detailed patient-, disease-, and treatment-related data, including toxicities, were captured at baseline, the beginning of each cycle, and each midcycle blood draw for up to 4 cycles of treatment. Primary outcomes included febrile neutropenia (FN), severe neutropenia without fever/infection, and relative dose intensity (RDI). Thirty-seven percent of patients were aged 65 years or older, 43.5% had an Eastern Cooperative Oncology Group performance status of 1 or greater, and 27% had 1 or more comorbidities. Reductions in RDI to less than 85% of standard in the first cycle were planned in 23.6% of patients, whereas primary colony-stimulating factor prophylaxis was used in 18.2%. In the first 3 cycles of treatment, 10.7% of patients experienced FN, with most of these events (58.9%) occurring in the first cycle. This first-cycle pattern was consistently observed despite wide variations in event rates by tumor type, disease stage, chemotherapy regimen and dose, and patient characteristics. Despite frequent planned reductions from standard RDI, the incidence of FN remains high in community oncology practice in the United States. Improved methods of pretreatment assessment of patient risk factors for neutropenia are needed.
Myeloid Growth Factors
Jeffrey Crawford, James Armitage, Lodovico Balducci, Charles Bennett, Douglas W. Blayney, Spero R. Cataland, David C. Dale, George D. Demetri, Harry P. Erba, James Foran, Alison G. Freifeld, Marti Goemann, Mark L. Heaney, Sally Htoy, Susan Hudock, Dwight D. Kloth, David J. Kuter, Gary H. Lyman, Laura Boehnke Michaud, Sarah C. Miyata, Martin S. Tallman, Saroj Vadhan-Raj, Peter Westervelt, and Michael K. Wong
NCCN Guidelines® Insights: Hodgkin Lymphoma, Version 2.2022
Featured Updates to the NCCN Guidelines
Richard T. Hoppe, Ranjana H. Advani, Weiyun Z. Ai, Richard F. Ambinder, Philippe Armand, Celeste M. Bello, Cecil M. Benitez, Weina Chen, Bouthaina Dabaja, Megan E. Daly, Leo I. Gordon, Neil Hansen, Alex F. Herrera, Ephraim P. Hochberg, Patrick B. Johnston, Mark S. Kaminski, Christopher R. Kelsey, Vaishalee P. Kenkre, Nadia Khan, Ryan C. Lynch, Kami Maddocks, Jonathan McConathy, Monika Metzger, David Morgan, Carolyn Mulroney, Sheeja T. Pullarkat, Rachel Rabinovitch, Karen C. Rosenspire, Stuart Seropian, Randa Tao, Pallawi Torka, Jane N. Winter, Joachim Yahalom, Joanna C. Yang, Jennifer L. Burns, Mallory Campbell, and Hema Sundar
Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.
Palliative Care Version 1.2016
Michael Levy, Thomas Smith, Amy Alvarez-Perez, Anthony Back, Justin N. Baker, Anna C. Beck, Susan Block, Shalini Dalal, Maria Dans, Thomas R. Fitch, Jennifer Kapo, Jean S. Kutner, Elizabeth Kvale, Sumathi Misra, William Mitchell, Diane G. Portman, Todd M. Sauer, David Spiegel, Linda Sutton, Eytan Szmuilowicz, Robert M. Taylor, Jennifer Temel, Roma Tickoo, Susan G. Urba, Elizabeth Weinstein, Finly Zachariah, Mary Anne Bergman, and Jillian L. Scavone
The NCCN Guidelines for Palliative Care provide interdisciplinary recommendations on palliative care for patients with cancer. The NCCN Guidelines are intended to provide guidance to the primary oncology team on the integration of palliative care into oncology. The NCCN Palliative Care Panel's recommendations seek to ensure that each patient experiences the best quality of life possible throughout the illness trajectory. Accordingly, the NCCN Guidelines outline best practices for screening, assessment, palliative care interventions, reassessment, and after-death care.
NCCN Guidelines Insights: Palliative Care, Version 2.2017
Maria Dans, Thomas Smith, Anthony Back, Justin N. Baker, Jessica R. Bauman, Anna C. Beck, Susan Block, Toby Campbell, Amy A. Case, Shalini Dalal, Howard Edwards, Thomas R. Fitch, Jennifer Kapo, Jean S. Kutner, Elizabeth Kvale, Charles Miller, Sumathi Misra, William Mitchell, Diane G. Portman, David Spiegel, Linda Sutton, Eytan Szmuilowicz, Jennifer Temel, Roma Tickoo, Susan G. Urba, Elizabeth Weinstein, Finly Zachariah, Mary Anne Bergman, and Jillian L. Scavone
The NCCN Guidelines for Palliative Care provide interdisciplinary recommendations on palliative care for patients with cancer. These NCCN Guidelines Insights summarize and provide context for the updated guidelines recommendations regarding hospice and end-of-life (EOL) care. Updates for 2017 include revisions to and restructuring of the algorithms that address important EOL concerns. These recommendations were revised to provide clearer guidance for oncologists as they care for patients with cancer who are approaching the transition to EOL care. Recommendations for interventions and reassessment based on estimated life expectancy were streamlined and reprioritized to promote hospice referrals and improved EOL care.