The National Comprehensive Cancer Network (NCCN) recently announced guidelines for the use of myeloid growth factors at their 2005 annual meeting, held March 16-19 in Hollywood Florida. The NCCN is a voluntary association of nineteen of the nation’s NCI designated Comprehensive Cancer Centers. Their primary focus is formulating guidelines for the treatment of cancer and its symptoms. The purpose of the annual meeting is to introduce and discuss new guidelines, and to review information pertinent to the modification of existing guidelines. Material presented at the NCCN meeting provides a useful review of the state-of-the-art in cancer therapy.
Guidelines for the use of myeloid growth factor have not been previously issued by the NCCN. Related guidelines exist for the treatment of patients who have developed fever and chemotherapy-induced neutropenia, and for prevention and treatment of cancer related anemia and fatigue. The complete set of supportive care and treatment related guidelines are available at .
Guidelines for the Use of Myeloproliferative Growth Factors
The NCCN Myeloid Growth Factor Panel introduced its first set of guidelines for the use of myeloid growth factors. Dr. Jeffrey Crawford, the panel’s chairman, introduced the new guideline on behalf of the panel. The guideline development committee confined their initial efforts to adult patients with solid tumors and non-myeloid malignancies. The panel determined that there was enough evidence of clinical benefit to recommend the use of growth factors in the first cycle or prophylactically in patients who are treated with:
- curative intent
- regimens with a high chance of neutropenia (greater than 20% chance)
- adjuvant chemotherapy with intent to augment surgical cure
- myelotoxic chemotherapy with the intent of prolongation of survival or quality of life improvement or symptom management
The panel recognized that for patients undergoing treatment with the goal of symptom management, “the use of high risk chemotherapy in this setting is a difficult decision and requires careful discussion between the physician and the patient. Other alternatives, such as the use of less myelosuppressive chemotherapy or dose reduction should be considered” (table 1).
For patients treated with a regimen carrying an intermediate chance of febrile neutropenia (between 10 and 20%), the panel recommended considering first cycle growth factor use based on patient and cancer-related factors (table 1).
Table 1 Recommendations of the NCCN Myeloid Growth Factor Panel
The potentially controversial feature of the new guideline is its utilization of the “20% rule;” that is, benefit to growth factor use with febrile neutropenia rates of greater than 20%. Though the panel was not specifically charged with economic or cost-benefit considerations, recent data suggests that use of the 20% threshold for febrile neutropenia prophylaxis is cost effective.,,,
Examples of specific regimens considered by the panel with a high risk of neutropenia are numerous. For more information, the complete guidelines are at .
Risk Factors Identified
Predictors of febrile neutropenic events are currently imprecise. The guideline suggests an iterative approach to re-assess growth factor use on subsequent cycles of the same chemotherapy regimen. If the patient did not develop febrile neutropenia or a dose-limiting neutropenic event, then repetition of the previous intervention (i.e. growth factor use or not, whatever was done on the previous cycle) was recommended. However, if a neutropenic event occurred, either dose reduction or growth factor use should be considered.
However, the panel did identify risk factors that physicians should consider when deciding whether or not to use growth factors. Treatment-related risk factors include:
- anthracycline-based chemotherapy
- planned dose intensity greater than 80%
- pre-existing neutropenia or lymphopenia
- extensive prior chemotherapy or concurrent radiotherapy.
Patient specific factors which elevate risk include:
- age over 65 years
- female gender
- poor performance status
- serum albumin less than 3.5 gm/dL
- no early or previous G-CSF use
- hepatic comorbidity
- history of neutropenia, or development of anemia on the first cycle ( i.e. Hgb drop of more than 0.83gm/dL).
Presence of open wounds or active, ongoing infections are considered risk factors for development of febrile neutropenia. Ethnicity is a risk factor for neutropenia and dose delay, but has not been shown to be a risk factor for febrile neutropenia or hospitalization.
Degree of Consensus for Specific Growth Factors
There was uniform concensus for the use of filgrastim and pegfilgrastim and lesser support for sagramostim use. The NCCN uses a system for reporting the level of concensus for a guideline recommendation that is a scale from category 1, representing uniform NCCN concensus, to category 3, which represents major disagreement among NCCN members. The panel reported category 1 evidence for filgrastim and pegfilgrastim, which is defined as uniform NCCN consensus based on high level evidence. Support for sagramostim use was category 2b, considered non-uniform NCCN consensus but no disagreement, based on low level evidence including clinical experience. The filgrastim and pegfilgrastim agents should start day two, the day after chemotherapy. Pegfilgrastim is administered once per chemotherapy cycle, and filgrastim through day 10 or until the absolute neutrophil count is greater than 2,000 per µL.
The high level evidence for the use of pegfilgrastim sited and discussed at the NCCN meeting is a study of “same day” pegfilgrastim dosing that was reported at the 2004 San Antonio Breast Cancer Symposium. In this small, randomized study, administration of pegfilgrastim on the same day of chemotherapy was reported to be associated with a lower incidence of hospitalization and neutropenia compared with the standard treatment of pegfilgrastim on the next day of chemotherapy in the adjuvant treatment of patients with node positive breast cancer. There was a 7% incidence of hospitalization for febrile neutropenia among patients treated with TAC (docetaxel, doxorubicin and cyclophosphamide) and next day pegfilgrastim compared with a 33% incidence of hospitalization for patients treated with same day pegfilgrastim. Same day pegfilgrastim resulted in similar febrile neutropenia hospitalization rates with TAC chemotherapy when no prophylactic growth factors were used.
Cancer and Treatment-Related Anemia
David Straus, M.D. reviewed new data on erythropoetic growth factors with a view to future modifications of the NCCN erythropoetic growth factor guidelines. Current NCCN guidelines suggest institution of an erythropoetic supportive care agent when a patient’s hemoglobin (Hgb) level falls below 10 gm/dL, and titration to maintain Hgb at 12 gm/dL. Monitoring of iron serum iron status prior to and during therapy is also recommended.
Three randomized trials which focus on therapy of mild anemia, defined as patients who are receiving chemotherapy and who have Hgb <10, have shown benefit to early initiation of therapy compared to later initiation of treatment.
Anemia in leukemia, lymphoma, myeloma, and CLL: Dr. Straus and his colleagues tested and enrolled leukemia, lymphoma, myeloma, or CLL patients with mild anemia (Hgb <10 gram/dL). They were randomly assigned, at the start of chemotherapy, to receive immediate therapy with epoetin alfa 40,000 units weekly or to wait until the Hgb dropped to less than 9 gm/dL to receive epoetin alfa. In the 269 patients, 85% of whom had non-Hodgkin lymphoma, only 19% in the group who were planned to receive epoetin alfa only after a drop in Hgb ever received epoetin. Among patients who received treatment immediately, 70% had a hematopoeitic response.
Anemia in non-small cell lung cancer: A second study, in chemotherapy naive non-small cell lung cancer patients, evaluated epoetin alfa 40,000 units weekly versus no epoetin alfa (control) in patients with entry Hgb between 11 and 15 grams/dL. Control patients received epoetin alfa if Hgb decreased to less than 10 grams/dL, and 45% of initially non-treated patients were switched to epoetin alfa therapy. Hgb was maintained throughout the study in the epoetin alfa group, whereas Hgb decreased to <10 gram/dL in 44% of control patients and 18% of epoetin alfa patients (p=0 .0001). The majority of late intervention patients never reached the target hemoglobin of 11 grams/dL. The investigators concluded that epoetin alfa is safe and effective in maintaining Hgb levels in lung cancer patients receiving first-line chemotherapy.
Anemia of cancer: A third study, on which a preliminary report was delivered at the 2003 American Society of Hematology annual meeting, was conducted in patients with the anemia of cancer, meaning they were not receiving chemotherapy and their anemia was . Intervention was darbepoetin alfa 3ug/kg every two weeks compared with observation. In an early analysis, patients on the intervention arm had a hematopoetic response of 81% and 26% for the non-intervention group.
Myeloid Growth Factors: Which Agent?
Dr. Straus next addressed new data on the choice of erythropoetic agent. He reviewed two small randomized trials comparing epoetin alpha and darbepoetin in chemotherapy-induced anemia. The trial sponsored by Amgen, the manufacturer of darbepoetin, was designed to validate a “Patient Satisfaction Questionnaire” in patients treated with either a specified dose of darbepoetin or epoetin alfa. A comparison of the relative efficacy of the two agents was included in the publication. A second trial, sponsored by the Orthobiotech, the marketers of epoetin alfa, also compared the two erythropoetic agents. The trials were not designed, nor were they powered to show superiority or even non-inferiority for either agent; they did show that both agents work in chemotherapy induced anemia.
Controversy remains regarding which agent and schedule is most effective and about whether the difference between the agents in speed of response is meaningful.
Immunotherapy improves survival in cholangiocarcinoma and other biliary tract cancers.
Immunotherapy improves survival in cholangiocarcinoma and other biliary tract cancers.
Notably, three new agents are in development and were discussed:
- ESA, a pegylated, dimeric peptide which was designed as an activating ligand to the cloned erythropoetin receptor
- Continuous erythropoetin receptor activator (CERA)
- FG-2216, an oral small molecule designed to stimulate endogenous erythropoeiten secretion
The myeloid growth factors, filgrastim, pegfilgrastim and sargramostim, should be considered for first cycle prophylaxis of febrile neutropenia in patients receiving curative-intent chemotherapy whose risk of developing febrile neutropenia is greater than 20%.
When deciding on first-cycle use in patients receiving chemotherapy with regimens associated with a 10 and 20% probability of causing neutropenia, physicians should consider treatment-, tumor- and patient-specific risk factors (previous neutropenia, planned relative dose intensity more than 80%, bone marrow involvement, poor performance status or nutrition, open wounds, active infection, etc.)
When deciding on use of myeloid growth factors on subsequent cycles, physicians should follow an iterative process with subsequent chemotherapy cycles, and reevaluate the occurrence of febrile neutropenia on previous cycles, the goals of therapy, and the dose of chemotherapy drug.
While randomized trials demonstrate symptomatic benefit of myeloid growth factors in the treatment of mild anemia (Hgb 10-12 gm/dL) and the 3 products (epoetin alfa, darbepoetin, epoetin beta) are all considered to be effective, there is no clinical data from a properly conducted clinical trial to convincingly show superiority or equivalence among these compounds. Also, controversy does still exist regarding the relative merits of a faster response and the dosing interval.
Research in the area of myeloid growth factors is active and ongoing, and includes the development of new agents that either have similar proposed mechanisms of action or novel mechanisms of action to the existing compounds are in clinical development.
 Vogel CL, Wojtukiewicz MZ, Carroll RR et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled phase III study. J Clin Oncol . 2005;23:1178-1184.
 Lyman GH, Kuderer N, Greene J, Balducci L. The economics of febrile neutropenia: implications for the use of colony-stimulating factors. Eur J Cancer . 1998;34:1857-1864.
 Lyman GH, Kuderer NM. The economics of the colony-stimulating factors in the prevention and treatment of febrile neutropenia. Crit Rev Oncol Hematol . 2004;50:129-146.
 Cosler LE, Calhoun EA, Agboola O, Lyman GH. 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. Pharmacotherapy . 2004;24:488-494.
 Lyman GH. Balancing the benefits and costs of colony-stimulating factors: a current perspective. Semin Oncol . 2003;30:10-17.
 Lyman GH, Delgado DJ. Risk and timing of hospitalization for febrile neutropenia in patients receiving CHOP, CHOP-R, or CNOP chemotherapy for intermediate-grade non-Hodgkin lymphoma. Cancer . 2003;98:2402-2409.
 Silber JH, Fridman M, Shpilsky A et al. Modeling the cost-effectiveness of granulocyte colony-stimulating factor use in early-stage breast cancer. J Clin Oncol . 16:2435-2444, 1998.
 Hershman D, Weinberg M, Rosner Z et al. Ethnic neutropenia and treatment delay in African American women undergoing chemotherapy for early-stage breast cancer. J Natl Cancer Inst . 2003;95:1545-1548.
 Kaufman PA, Paroly W, Rinaldi DA, and Sonnier S. Randomized double-blind phase 2 study evaluating same-day vs next-day administration of pegfilgrastim with docetaxel, doxorubicin, and cyclophosphamide (TAC) in women with early stage and advanced breast cancer [abstract]. Breast Cancer Res Treat . 2004;88:Abstract # 1054.
 Nabholtz JM, Pienkowski T, Mackey J, Pawlicki M Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 study. 2002.
 Ozer H, Armitage JO, Bennett CL et al. 2000 update of recommendations for the use of hematopoietic colony-stimulating factors: evidence-based, clinical practice guidelines. American Society of Clinical Oncology Growth Factors Expert Panel. J Clin Oncol . 2000;18:3558-3585.
 Clark O, Lyman GH, Castro AA, Clark LGO. Colony stimulating factors for chemotherapy induced febrile neutropenia. 2005. http://www.cochrane.org/cochrane/revabstr/AB003039.htm, The Cochrane Library.
 Straus DJ. Epoetin alfa therapy for patients with hematologic malignancies and mild anemia. Clin Lymphoma . 2003;4(1):S13-S17.
 Crawford J, Robert F, Perry M, and Belani CP. Epoetin alfa 40,000 u once weekly maintains hemoglobin in advanced non-small-cell lung cancer patients receiving first-line chemotherapy [abstract]. Proc Am Soc Clin Oncol. 2003;22:628 Abstract #2527.
 Charu V, Belani CP, Gill A et al. Every-2-Week (Q2W) Dosing of Darbepoetin Alfa in Patients with Anemia of Cancer (AOC): Interim Analysis of a Randomized, Controlled Study [abstract]. Blood. 2003;102:Abstract #1816.
 Schwartzberg LS, Yee LK, Senecal FM et al. A randomized comparison of every-2-week darbepoetin alfa and weekly epoetin alfa for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic cancer. Oncologist . 2004;9:696-707.
 Waltzman RJ and Williams D. Head-to-Head Comparison of Epoetin Alfa (EPO) 40,000 U QW vs Darbepoetin Alfa (DARB) 200 ?g Q2W in Anemic Cancer Patients Receiving Chemotherapy (CT): Final Results of a Planned Interim Analysis (IA [abstract]. Blood. 2004;104:Abstract #4233.
 Woodburn KW, Fan Q, and Leuther KK. Preclinical Evaluation of Hematide™, a Novel Erythropoietic Receptor Agonist for the Treatment of Anemia Caused by Kidney Disease [abstract]. Blood . 2004;104:Abstract #2904.
 Osterborg A, Hellmann A, Steegman JL, and Couban S. CERA (Continuous Erythropoietin Receptor Activator): Dose-Response Trial of Subcutaneous (SC) Administration Once Every 3 Weeks (Q3W) to Patients with Aggressive Non-Hodgkin’s Lymphoma and Anemia Receiving Chemotherapy [abstract]. Blood. 2004;104:Abstract #4225.
 Urquilla P, Fong A, and Oksanen S. Upregulation of Endogenous Erythropoietin (EPO) in Healthy Subjects by Inhibition of Hypoxia Inducible Factor (HIF) Prolyl Hydroxylase [abstract]. Blood . 2004;104:Abstract #174.