These recommendations include a restatement of previous recommendations as well as several important modifications and additions to the previous guidelines based on several additional clinical trials and newly introduced agents.
—Gary H. Lyman, MD, MPH
Neutropenic complications remain the main dose-limiting toxicity of cancer chemotherapy treatment and are associated with considerable morbidity, mortality, and costs.1 Although patients who have experienced a prior neutropenic event are at increased risk of subsequent events, several studies have shown that the risk of the initial neutropenic event is greatest in the first cycle, when most patients are receiving full-dose chemotherapy.2-4 Recombinant white blood cell growth factors or colony-stimulating factors have been demonstrated to reduce the risk and consequences of neutropenic complications and enable safe delivery of myelosuppressive chemotherapy at full dose on schedule in multiple randomized controlled trials.5
ASCO published its first clinical practice guideline on the use of hematopoietic colony-stimulating factors in 1994. These guidelines have been updated periodically, including in 1996, 1997, 2000, and 2006.6 In the interim, several additional guidelines on the use of colony-stimulating factors were updated.7,8
In July 2015, another guideline update based on a comprehensive and systematic review of the medical literature since 2005 was published in the Journal of Clinical Oncology.9 A complete summary of the recommendations appears in this issue of The ASCO Post. These recommendations include a restatement of previous recommendations as well as several important modifications and additions to the previous guidelines based on several additional clinical trials and newly introduced agents. The recommendations are applicable to patients with a broad range of adult and pediatric malignancies including solid tumors and lymphoma.
Restatement of Previous Recommendations
Recommendations with little or no modification based on the updated review include primary prophylaxis, starting shortly after completion of the initial and subsequent cycles of chemotherapy in patients with an approximately ≥ 20% risk of febrile neutropenia based on treatment-, disease-, and patient-specific risk factors for febrile neutropenia, as well as in patients receiving dose-dense chemotherapy regimens. This recommendation is supported by well-designed clinical trials. Although evidence has shown that colony-stimulating factor prophylaxis may reduce early treatment-related as well as long-term mortality, this recommendation was based on the reduction in risk of febrile neutropenia as a clinically meaningful outcome in patients receiving cancer chemotherapy.5,10
While encouraging the further development and validation of risk prediction models, the guidelines updated a list of recognized patient risk factors for the development of febrile neutropenia, as well as those predictive of a poor clinical outcome resulting from febrile neutropenia or infection.9,11,12 Specifically, the update panel recommended the use of prophylactic colony-stimulating factors in patients aged ≥ 65 years receiving potentially curative chemotherapy for diffuse aggressive non-Hodgkin lymphoma (NHL), especially in the presence of comorbidities.13,14 Secondary prophylaxis in subsequent cycles is again recommended in patients who experience febrile neutropenia in a prior cycle of the same chemotherapy when a reduction in dose, delay in treatment, or an alternative less-myelosuppressive regimen might adversely impact important patient outcomes.
The panel again recommended against the routine use of colony-stimulating factors in patients with afebrile neutropenia, as well as in most patients with existing febrile neutropenia receiving antibiotics, unless there is high risk for infectious complications. The use of colony-stimulating factors continues to be recommended for peripheral blood cell mobilization, as well as to support patients undergoing stem cell transplantation.
The panel presented similar recommendations for appropriate use of these agents in pediatric patients with cancer but specifically recommended against their use in children with nonrelapsed acute lymphoblastic leukemia or acute myeloid leukemia. The guidelines do not address the use of colony-stimulating factors in adults with acute myeloid leukemia or myelodysplastic syndromes. On the basis of formal consensus, use of the colony-stimulating factors is recommended in patients exposed to potentially lethal doses of total-body radiation.9
Modifications or Additions
At the same time, the updated white blood cell growth factor guidelines have modified or added to previous guideline recommendations. After a review of the limited and conflicting available evidence, the panel concluded that the value of dose-dense regimens with colony-stimulating factor support has been demonstrated in patients receiving adjuvant systemic chemotherapy for early-stage breast cancer but not in patients with NHL, and, therefore, cannot be routinely recommended in the latter.15,16 However, evidence supporting colony-stimulating factor support of patients receiving high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin for urothelial cancer was considered sufficient for recommendation.17
Finally, although the data are rapidly evolving and variable, the panel concluded that filgrastim, pegfilgrastim, tbo-filgrastim, and filgrastim-sndz could all be used for the prevention of treatment-related febrile neutropenia. The panel concluded that in addition to filgrastim and pegfilgrastim, newly introduced agents, either through a conventional approval mechanism (tbo-filgrastim) or through a new approval process for biosimilars (filgrastim-sndz), can be used to reduce the risk of febrile neutropenia.
Limited data have suggested that pegfilgrastim may be more effective than filgrastim in reducing the risk of febrile neutropenia.18,19 The choice of agent will depend upon clinical experience, patient convenience, and cost. The panel reiterated recommendations for administration of the colony-stimulating factors to start within 1 to 3 days after administration of chemotherapy.9 ■
Disclosure: Dr. Lyman is a member of the ASCO Guideline Panel on the Use of White Blood Cell Growth Factors and principal investigator on a research grant to the Fred Hutchinson Cancer Research Center from Amgen.
1. Kuderer NM, Dale DC, Crawford J, et al: Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 106:2258-2266, 2006.
2. Crawford J, Dale DC, Kuderer NM, et al: Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: The results of a prospective nationwide study of oncology practice. J Natl Compr Canc Netw 6:109-118, 2008.
3. 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 98:2402-2409, 2003.
4. Lyman GH, Morrison VA, Dale DC, et al: Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin’s lymphoma receiving CHOP chemotherapy. Leuk Lymphoma 44:2069-2076, 2003.
5. Kuderer NM, Dale DC, Crawford J, Lyman GH: Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: A systematic review. J Clin Oncol 25:3158-3167, 2007.
6. Smith TJ, Khatcheressian J, Lyman GH, et al: 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 24:3187-3205, 2006.
7. Aapro MS, Bohlius J, Cameron DA, et al: 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer 47:8-32, 2011.
8. Crawford J, Armitage J, Balducci L, et al: Myeloid growth factors. J Natl Compr Canc Netw 11:1266-1290, 2013.
9. Smith TJ, Bohlke K, Lyman GH, et al: Recommendations for the use of WBC growth factors: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 33:3199-3212, 2015.
10. Lyman GH, Dale DC, Wolff DA, et al: Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: A systematic review. J Clin Oncol 28:2914-2924, 2010.
11. Lyman GH, Kuderer NM, Crawford J, et al: Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy. Cancer 117:1917-1927, 2011.
12. Lyman GH, Abella E, Pettengell R: Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review. Crit Rev Oncol Hematol 90:190-199, 2014.
13. Balducci L, Al-Halawani H, Charu V, et al: Elderly cancer patients receiving chemotherapy benefit from first-cycle pegfilgrastim. Oncologist 12:1416-1424, 2007.
14. Shayne M, Culakova E, Poniewierski MS, et al: Risk factors for in-hospital mortality and prolonged length of stay in older patients with solid tumor malignancies. J Geriatr Oncol 4:310-318, 2013.
15. Cunningham D, Hawkes EA, Jack A, et al: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: A phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381:1817-1826, 2013.
16. Delarue R, Tilly H, Mounier N, et al: Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): A randomised phase 3 trial. Lancet Oncol 14:525-533, 2013.
17. Sternberg CN, de Mulder P, Schornagel JH, et al: Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 42:50-54, 2006.
18. Cooper KL, Madan J, Whyte S, et al: Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: Systematic review and meta-analysis. BMC Cancer 11:404, 2011.
19. Pinto L, Liu Z, Doan Q, et al: Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: A meta-analysis of randomized controlled trials. Curr Med Res Opin 23:2283-2295, 2007.
ASCO has issued a clinical practice guideline update on use of hematopoietic colony-stimulating factors, as reported in the Journal of Clinical Oncology by Thomas J. Smith, MD, FACP, FASCO, FAAHMP, and colleagues.1 This update to the ASCO 2006 guideline was based on a systematic review of...