Neutropenia Risk Models in Oncology

A number of novel and targeted agents for treating cancer have been introducedin recent years. Nevertheless, chemotherapy remains the mainstayof 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 concernin 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.[1]The risk of infection correlates with both the depth and the duration of neutropenia.Febrile neutropenia is treated as a potentially life-threatening emergency, withimmediate hospitalization and prompt administration of broad-spectrum antibioticsrepresenting the standard of care.[2] In addition, patients with severe neutropeniaand febrile neutropenia have lower quality of life and physical well-being.[3-5]Perhaps the most important potential effects of chemotherapy-induced neutropeniaare subsequent reductions in chemotherapy dose intensity, due to dosereductions and treatment delays that are intended to lessen the incidence of neutropeniaand its complications.[6] Clinical studies have demonstrated the importanceof maintaining chemotherapy dose intensity in long-term survival in patients withresponsive and potentially curable malignanices.[7-9]Prophylactic colony-stimulating factor (CSF) has been shown to reduce theseverity and duration of severe neutropenia and the risk of febrile neutropenia, aswell as enable the delivery of full chemotherapy dose intensity.[10-13] Guidelinesestablished by the American Society of Clinical Oncology (ASCO) for use of theCSFs are based primarily on the expected risk of febrile neutropenia associated withspecific chemotherapy regimens. Primary prophylaxis with CSF is recommendedwhen the chemotherapy regimen is associated with a 40% likelihood of hospitalizationfor febrile neutropenia.[14] In fact, improved economic analyses suggest that acost savings is likely with the use of prophylactic CSF when the risk of febrileneutropenia exceeds 20%. This approach requires assessing the myelosuppressivepotential of the chemotherapy regimen; although some regimens are clearly moremyelosuppressive than others, the true incidence of severe neutropenia associatedwith most regimens is underreported and ill-defined.[15]The articles in this supplement discuss an alternative approach to the effectiveand cost-effective use of CSF through the development and application of clinicalpredictive or risk models. In the first article, I discuss such predictive models, whichattempt to identify patients at increased risk of neutropenic complications toenable the targeted use of CSF in those patients, and not in those at low risk andthus less likely to benefit. Risk models reported to date have been developedretrospectively, in small numbers of patients, and only a few of them have beenvalidated in separate patient populations. Consequently, a large nationwide patientregistry has been developed to gather prospective data for creating more accurateand valid risk models for routine clinical use.[16]The second and third articles in this supplement focus on specific clinicalsettings: early-stage breast cancer (Chau Dang, Monica Fornier, and CliffordHudis) and non-Hodgkin's lymphoma (Andrew Zelenetz). Because of the strongrelation between chemotherapy dose and outcome in these two cancers, togetherwith the fact that myelosuppression is a frequent cause of dose alterations, riskmodels have been most frequently developed for these cancers.The final article, by Lodovico Balducci, discusses prophylaxis with CSF inelderly patients. Studies have repeatedly found that age is a risk factor for neutropeniaand its complications[17] and that the risk is highest in the early cycles ofchemotherapy.[18-20] Consequently, chemotherapy is often initiated at lower,substandard doses in the elderly in an effort to minimize myelosuppression andavert neutropenia-a practice that may be responsible for the poorer outcomes inolder patients.[6,21] Elderly patients should therefore be considered a specialpopulation in whom early use of prophylactic CSF should be considered.In addition to age, other patient-, disease-, and treatment-related measures areassociated with an increased risk of neutropenia and its complications. Oncevalidated, predictive models will be used for selecting such high-risk patients forCSF prophylaxis. Subsequent studies will be needed to evaluate the impact oftargeted CSF prophylaxis using these models on the clinical, quality-of-life, andeconomic outcomes of cancer treatment.

Disclosures:

The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

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 antimicrobialagents 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 gradeIV chemotherapy-induced neutropenia (CIN) (abstract 2920). Proc Am Soc Clin Oncol 21:275b,2002.

5.

Lyman GH, Kuderer NM: Filgrastim in patients with neutropenia: Potential effects onquality of life. Drugs 62(suppl 1):65-78, 2002.

6.

Lyman GH, Dale D, Crawford J: Incidence and predictors of low dose intensity inadjuvant breast cancer chemotherapy: A nationwide study of community practices. J Clin Oncol.In press.

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 JMed 332:901-906, 1995.

8.

Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants ofoutcome in the adjuvant treatment of breast cancer. The Cancer and Leukemia Group B. J NatlCancer Inst 90:1205-1211, 1998.

9.

Kwak LW, Halpern J, Olshen RA, et al: Prognostic significance of actual dose intensity indiffuse large-cell lymphoma: Results of a tree-structured survival analysis. J Clin Oncol 8:963-977, 1990.

10.

Crawford J, Ozer H, Stoller R, et al: Reduction by granulocyte colony-stimulating factorof fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N EnglJ Med 325:164-170, 1991.

11.

Trillet-Lenoir V, Green J, Manegold C, et al: Recombinant granulocyte colony stimulatingfactor reduces the infectious complications of cytotoxic chemotherapy. Eur J Cancer 29A:319-324, 1993.

12.

Holmes FA, O’Shaughnessy JA, Vukelja S, et al: Blinded, randomized, multicenter studyto evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunctto chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol20:727-731, 2002.

13.

Green MD, Koelbl H, Baselga J, et al: A randomized double-blind multicenter phase IIIstudy of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receivingmyelosuppressive chemotherapy. Ann Oncol 14:29-35, 2003.

14.

Ozer H, Armitage JO, Bennett CL, et al: 2000 update of recommendations for the use ofhematopoietic colony-stimulating factors: Evidence-based, clinical practice guidelines. AmericanSociety 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 1:440-454,2003.

16.

Dale DC, Wolff D, Agboola O, et al: Development of a risk model for neutropeniccomplications based on a prospective nationwide registry (abstract 2229). Proc Am Soc Clin Oncol22:554, 2003.

17.

Bastion Y, Blay JY, Divine M, et al: Elderly patients with aggressive non-Hodgkin’slymphoma: Disease presentation, response to treatment, and survival-A Groupe d’Etude desLymphomes de l’Adulte study on 453 patients older than 69 years. J Clin Oncol 15:2945-2953,1997.

18.

Lyman GH, Morrison VA, Dale DC, et al: Risk of febrile neutropenia among patients withintermediate-grade non-Hodgkin’s lymphoma receiving CHOP chemotherapy. Leuk Lymphoma44(12):2069-2076, 2003.

19.

Caggiano V, Stolshek B, Delgado D, et al: First and all cycle febrile neutropeniahospitalizations (FNH) and costs in intermediate grade non-Hodgkin’s lymphoma (IGL) patientson 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 inelderly patients with aggressive non-Hodgkin’s lymphoma: Results of a multivariate analysis. JClin Oncol 16:2065-2069, 1998.

21.

Dixon DO, Neilan B, Jones SE, et al: Effect of age on therapeutic outcome in advanceddiffuse histiocytic lymphoma: The Southwest Oncology Group experience. J Clin Oncol 4:295-305, 1986.