A number of novel and targeted agents for treating cancer have been introduced
in recent years. Nevertheless, chemotherapy remains the mainstay
of treatment in the majority of patients, and myelosuppression-
especially neutropenia-represents the primary dose-limiting toxicity of chemotherapy.
Therefore, chemotherapy-induced neutropenia remains a central concern
in the safe and effective delivery of chemotherapy.
The consequences of chemotherapy-induced neutropenia are far-reaching,
from short-and long-term clinical effects to economic and quality-of-life issues.
The risk of infection correlates with both the depth and the duration of neutropenia.
Febrile neutropenia is treated as a potentially life-threatening emergency, with
immediate hospitalization and prompt administration of broad-spectrum antibiotics
representing the standard of care. In addition, patients with severe neutropenia
and febrile neutropenia have lower quality of life and physical well-being.[3-5]
Perhaps the most important potential effects of chemotherapy-induced neutropenia
are subsequent reductions in chemotherapy dose intensity, due to dose
reductions and treatment delays that are intended to lessen the incidence of neutropenia
and its complications. Clinical studies have demonstrated the importance
of maintaining chemotherapy dose intensity in long-term survival in patients with
responsive and potentially curable malignanices.[7-9]
Prophylactic colony-stimulating factor (CSF) has been shown to reduce the
severity and duration of severe neutropenia and the risk of febrile neutropenia, as
well as enable the delivery of full chemotherapy dose intensity.[10-13] Guidelines
established by the American Society of Clinical Oncology (ASCO) for use of the
CSFs are based primarily on the expected risk of febrile neutropenia associated with
specific chemotherapy regimens. Primary prophylaxis with CSF is recommended
when the chemotherapy regimen is associated with a 40% likelihood of hospitalization
for febrile neutropenia. In fact, improved economic analyses suggest that a
cost savings is likely with the use of prophylactic CSF when the risk of febrile
neutropenia exceeds 20%. This approach requires assessing the myelosuppressive
potential of the chemotherapy regimen; although some regimens are clearly more
myelosuppressive than others, the true incidence of severe neutropenia associated
with most regimens is underreported and ill-defined.
The articles in this supplement discuss an alternative approach to the effective
and cost-effective use of CSF through the development and application of clinical
predictive or risk models. In the first article, I discuss such predictive models, which
attempt to identify patients at increased risk of neutropenic complications to
enable the targeted use of CSF in those patients, and not in those at low risk and
thus less likely to benefit. Risk models reported to date have been developed
retrospectively, in small numbers of patients, and only a few of them have been
validated in separate patient populations. Consequently, a large nationwide patient
registry has been developed to gather prospective data for creating more accurate
and valid risk models for routine clinical use.
The second and third articles in this supplement focus on specific clinical
settings: early-stage breast cancer (Chau Dang, Monica Fornier, and Clifford
Hudis) and non-Hodgkin's lymphoma (Andrew Zelenetz). Because of the strong
relation between chemotherapy dose and outcome in these two cancers, together
with the fact that myelosuppression is a frequent cause of dose alterations, risk
models have been most frequently developed for these cancers.
The final article, by Lodovico Balducci, discusses prophylaxis with CSF in
elderly patients. Studies have repeatedly found that age is a risk factor for neutropenia
and its complications and that the risk is highest in the early cycles of
chemotherapy.[18-20] Consequently, chemotherapy is often initiated at lower,
substandard doses in the elderly in an effort to minimize myelosuppression and
avert neutropenia-a practice that may be responsible for the poorer outcomes in
older patients.[6,21] Elderly patients should therefore be considered a special
population in whom early use of prophylactic CSF should be considered.
In addition to age, other patient-, disease-, and treatment-related measures are
associated with an increased risk of neutropenia and its complications. Once
validated, predictive models will be used for selecting such high-risk patients for
CSF prophylaxis. Subsequent studies will be needed to evaluate the impact of
targeted CSF prophylaxis using these models on the clinical, quality-of-life, and
economic outcomes of cancer treatment.
1. Crawford J, Dale DC, Lyman GH: Chemotherapy-induced neutropenia: Risks, consequences,
and new directions for its management. Cancer. In press.
2. Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the use of antimicrobial
agents in neutropenic patients with cancer. Clin Infect Dis 15;34:730-751, 2002.
3. Fortner BV, Solshek B, Schwartzberg LS, et al: Decline in absolute neutrophil count
(ANC) is associated with lower quality of life (QOL) in cancer patients receiving docetaxel
(abstract 2808). Proc Am Soc Clin Oncol 21:247b, 2002.
4. Okon TA, Fortner BV, Schwartzberg L, et al: Quality of life (QOL) in patients with grade
IV chemotherapy-induced neutropenia (CIN) (abstract 2920). Proc Am Soc Clin Oncol 21:275b,
5. Lyman GH, Kuderer NM: Filgrastim in patients with neutropenia: Potential effects on
quality of life. Drugs 62(suppl 1):65-78, 2002.
6. Lyman GH, Dale D, Crawford J: Incidence and predictors of low dose intensity in
adjuvant breast cancer chemotherapy: A nationwide study of community practices. J Clin Oncol.
7. Bonadonna G, Valagussa P, Moliterni A, et al: Adjuvant cyclophosphamide, methotrexate,
and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J
Med 332:901-906, 1995.
8. Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of
outcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J Natl
Cancer Inst 90:1205-1211, 1998.
9. Kwak LW, Halpern J, Olshen RA, et al: Prognostic significance of actual dose intensity in
diffuse large-cell lymphoma: Results of a tree-structured survival analysis. J Clin Oncol 8:963-
10. Crawford J, Ozer H, Stoller R, et al: Reduction by granulocyte colony-stimulating factor
of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl
J Med 325:164-170, 1991.
11. Trillet-Lenoir V, Green J, Manegold C, et al: Recombinant granulocyte colony stimulating
factor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 29A:319-
12. Holmes FA, O’Shaughnessy JA, Vukelja S, et al: Blinded, randomized, multicenter study
to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct
to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol
13. Green MD, Koelbl H, Baselga J, et al: A randomized double-blind multicenter phase III
study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving
myelosuppressive chemotherapy. Ann Oncol 14:29-35, 2003.
14. 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 18:3558-3585, 2000.
15. Dale DC, McCarter GC, Crawford J, et al: Myelotoxicity and dose intensity of chemotherapy:
Reporting practices from randomized clinical trials. J Natl Compr Cancer Netw 1:440-454,
16. Dale DC, Wolff D, Agboola O, et al: Development of a risk model for neutropenic
complications based on a prospective nationwide registry (abstract 2229). Proc Am Soc Clin Oncol
17. Bastion Y, Blay JY, Divine M, et al: Elderly patients with aggressive non-Hodgkin’s
lymphoma: Disease presentation, response to treatment, and survival—A Groupe d’Etude des
Lymphomes de l’Adulte study on 453 patients older than 69 years. J Clin Oncol 15:2945-2953,
18. 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
19. Caggiano V, Stolshek B, Delgado D, et al: First and all cycle febrile neutropenia
hospitalizations (FNH) and costs in intermediate grade non-Hodgkin’s lymphoma (IGL) patients
on standard-dose CHOP therapy (abstract 1810). Blood 98:431a, 2001.
20. Gomez H, Hidalgo M, Casanova L, et al: Risk factors for treatment-related death in
elderly patients with aggressive non-Hodgkin’s lymphoma: Results of a multivariate analysis. J
Clin Oncol 16:2065-2069, 1998.
21. Dixon DO, Neilan B, Jones SE, et al: Effect of age on therapeutic outcome in advanced
diffuse histiocytic lymphoma: The Southwest Oncology Group experience. J Clin Oncol 4:295-