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Risk Models for Predicting Chemotherapy-Induced Neutropenia

Health Services and Outcomes Research Program, James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA

Correspondence: Correspondence: Gary H. Lyman, M.D., M.P.H., F.R.C.P. (Edin), University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 704, Rochester, New York 14642, USA. Telephone: 585-275-3335; Fax: 585-276-1885; e-mail: Gary_Lyman{at}urmc.rochester.edu

	ABSTRACT

Top Abstract Introduction Risk Factors for CIN Risk Factors for CIN... Risk Models Versus Risk... Conditional Versus Unconditional... Validation of Risk Models Limitations of Current Risk... Risk Models Developed from... Conclusions Disclosure of Potential... References ADDITIONAL READING

 
Neutropenia and its complications, including febrile neutropenia, are major dose-limiting toxicities of systemic cancer chemotherapy. A number of studies have attempted to identify risk factors for neutropenia and its consequences to develop predictive models capable of identifying patients at greater risk for such complications and to guide more effective and cost-effective applications of the colony-stimulating factors. A systematic review of the literature showed that age, performance status, nutritional status, chemotherapy dose intensity, and low baseline blood cell counts were associated with the risk of severe and febrile neutropenia or reduced chemotherapy dose intensity in multivariate analysis in two or more studies. Similarly, age, diagnosis of leukemia or lymphoma, high temperature or low blood pressure at admission, and i.v. site infection along with low blood cell counts and organ dysfunction were associated with serious medical complications of febrile neutropenia, including bacteremia and death. The available risk model studies, however, had several limitations, including retrospective analyses of small study populations lacking independent validation, frequent missing values, and differences in the predictive factors considered. To overcome the limitations of previous studies, efforts are under way to develop and validate risk models based on large prospective studies in representative populations of patients receiving systemic chemotherapy.

Key Words. Neutropenia • Toxicities • Colony-stimulating factors • Risk model • Chemotherapy

	INTRODUCTION

Top Abstract Introduction Risk Factors for CIN Risk Factors for CIN... Risk Models Versus Risk... Conditional Versus Unconditional... Validation of Risk Models Limitations of Current Risk... Risk Models Developed from... Conclusions Disclosure of Potential... References ADDITIONAL READING

 
Chemotherapy-induced neutropenia (CIN) is the major dose-limiting toxicity of systemic cancer chemotherapy, and it is associated with substantial morbidity, mortality, and costs. Neutropenia may result in fever and neutropenia, or febrile neutropenia (FN), often necessitating hospitalization for evaluation and empiric broad-spectrum antibiotics. Such complications often result in dose reductions or treatment delays, which may compromise clinical outcomes [1–5]. The prophylactic use of colony-stimulating factors (CSFs) can reduce the risk, severity, and duration of both severe and febrile neutropenia [6–11]. Despite these benefits, CSFs are not administered to all patients receiving myelosuppressive chemotherapy because of the costs associated with their routine use. The selective use of CSFs in patients at greater risk for neutropenic complications may, however, enhance their cost-effective use by directing treatment toward those patients who are most likely to benefit.

The risk of severe and febrile neutropenia is usually based on the treatment regimen. A survey of the literature on randomized clinical trials of chemotherapy in patients with early-stage breast cancer (ESBC) and non-Hodgkin’s lymphoma (NHL) has shown, however, that the rates of myelosuppression and relative dose intensity (RDI) are underreported. When reported, the rates with the same and similar regimens varied greatly, making it difficult to determine the actual risk for neutropenic complications associated with common chemotherapy regimens [12]. Differences in the reported rates of neutropenic complications may relate to differences in study patient populations as well as the delivered dose intensity. Treatment dose intensity was reported with even less consistency, making it very difficult to interpret differences in reported rates of toxicity or treatment efficacy.

Early estimates of the threshold of risk at which the prophylactic use of CSFs becomes cost saving have been provided by economic models based on cost minimization using itemized, fixed costs of hospitalization for FN. These early models showed that the use of CSFs was cost saving when the risk for hospitalization for FN exceeded 40%; later models that are based on more current, direct costs and that include some indirect costs have shown that appropriate thresholds are closer to 20% [13,14]. Clearly, however, models based on average population risk estimates and the presumed myelosuppressive potential of the chemotherapy regimen may not be the most effective way for determining which patients should be offered CSF support. Therefore, recent efforts to increase the cost-effectiveness of the use of CSFs have focused on identifying patients at greater risk for neutropenic events, who are most likely to benefit from CSF prophylaxis. The development of clinical prediction or risk models for neutropenia and its complications based on risk factors should enable the identification of patients at greatest risk for these complications and the more targeted and cost-effective application of appropriate supportive care measures, such as the CSFs, in those at greatest need, who are most likely to benefit [15].

To identify risk factors associated with neutropenia and its complications, a systematic review of the literature was undertaken using electronic databases, including MED-LINE, EMBASE, and the Cochrane Library as well as references from relevant articles that were identified. Search terms included neutropenia, febrile neutropenia, risk factors, risk models, and predictive models. The studies that were selected reported multivariate risk models of neutropenic events or complications as well as RDI in patients receiving systemic cancer chemotherapy. In these studies, neutropenia was generally defined as an absolute neutrophil count (ANC) <1 x 10⁹/l (grade 3 and 4) or ANC <0.5 x 10⁹/l (grade 4). FN was defined as severe neutropenia (grade 3 or higher) with temperature >38.2°C. Dose intensity was defined as dose administered per unit of time, for example, mg/m² per week. In turn, the average RDI was defined as the ratio of the administered dose intensity to the standard dose intensity averaged across drugs in a regimen.

	RISK FACTORS FOR CIN

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Studies reviewed in this article showed risk factors for CIN or leukopenia (Table 1), FN (Table 2), and RDI (Table 3) in patients with NHL [16–22], ESBC [22–26], and other malignancies [27–29]. In these studies, advanced age, female sex, poor performance status, poor nutritional status, and low baseline and first-cycle nadir blood cell counts along with high chemotherapy dose intensity were all significant predictors of neutropenic events (Fig. 1). In patients with NHL, a high lactate dehydrogenase (LDH) level and the presence of bone marrow involvement were also significant. Studies that assessed risk factors for the consequences of neutropenia, including serious medical complications and mortality, were in patients with solid tumors, leukemias, and lymphomas in adults [30–38] and in children [39–43]. Significant predictors for neutropenic complications—including death (Table 4), bacteremia (Table 5), and length of hospital stay 10 days (Table 6)—were advanced age, hematologic malignancies, greater disease burden, high temperature and low blood pressure on admission, pneumonia, i.v. site infection, low blood cell counts, and organ dysfunction.

View larger version (37K): [in this window] [in a new window]   Figure 1. Risk factors for chemotherapy-induced neutropenia and its complications identified from published clinical prediction models.

View this table: [in this window] [in a new window]   Table 6. Risk factors for length of stay 10 days by study: multivariate model results (odds ratios)

Disease-Specific Risk Factors

Tumor Type
Patients with hematologic malignancies are at greater risk for neutropenic complications than patients with solid tumors because of the underlying disease process as well as the intensity of the treatment that is required [30,31]. Consistent with these findings, an analysis of data from patients hospitalized with FN in the 120 hospitals of the University HealthSystem Consortium showed that the duration of hospitalization as well as inpatient mortality were significantly greater in patients with leukemia than in patients with solid tumors (p < .001 for both) [32].

Advanced Disease and Uncontrolled Cancer
Both advanced disease and uncontrolled cancer were significant predictors of RDI, hospitalization for FN, and serious neutropenic complications, including death [21, 26, 33, 34].

Patient-Specific Risk Factors

Age
Ten studies found higher age to be a general risk factor for the development of severe neutropenia [18–24] and other neutropenic complications [30, 32, 33]. Advanced age is a particularly important independent risk factor, since older patients are often treated with lower chemotherapy doses to minimize the occurrence of neutropenic complications. Since older patients with cancer can obtain the same benefit from aggressive chemotherapy as younger patients [44], effective management of the risk of neutropenia is crucial to make it possible to administer full-dose chemotherapy in this population.

Performance Status
Three studies have shown that, in addition to age, poor performance status is a significant risk factor for chemotherapy-induced neutropenia [16, 18, 27]. In older patients, physiologic age or frailty may be a more accurate predictor of risk than chronologic age [45].

Comorbidities
The presence of comorbid conditions with cancer has been shown to increase the risk for neutropenia and its complications. Renal disease and heart disease have been shown to increase the risk for FN and reduced RDI in patients with NHL [19,20]. In patients with breast cancer, liver disease along with kidney and heart disease increased the risk for severe neutropenia and FN [22]. Similarly, comorbidities such as hypertension, chronic obstructive pulmonary disease, pneumonia, prior fungal infection, and sepsis have been shown to increase the risk for serious neutropenic complications, including prolonged hospitalizations for FN and death [30, 32, 34, 38].

Laboratory Abnormalities
Blood cell counts and chemistry analyses may indicate either the extent of disease, comorbid conditions, or the impact of cytotoxic chemotherapy. Many of these laboratory abnormalities have been identified as predictors for CIN and its complications.

We have reported that pretreatment WBCs are predictive of both FN and an RDI <85% in patients with ESBC [22]. Pretreatment hemoglobin levels <12 g/dl are also predictors of severe neutropenia or FN in cycle 1 [19,22]. One study in patients with aggressive NHL treated with cyclophosphamide, doxorubicin (Adriamycin^®; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com), vincristine (Oncovin^®; Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com), and prednisone (Deltasone^®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) (CHOP) also found that a serum albumin concentration of 35 g/l or less, an LDH level greater than the upper limit of normal, and bone marrow involvement of the lymphoma were all significant predictors of life-threatening neutropenia and FN [17]. The predictive value of high LDH levels was also determined in another study in patients with NHL, by Kloess et al. [18].

Conditional risk models have used patient responses in the first cycle of chemotherapy to predict the occurrence of neutropenia and its complications in subsequent cycles. Three studies have shown the predictive value of the first-cycle nadir in leukocyte counts [25, 27, 29] and decreases in hemoglobin or platelet levels [25,27] for predicting neutropenic complications in later cycles. An ANC <0.1 x 10⁹/l is also a significant predictor of serious medical complications [33].

Treatment-Specific Risk Factors

Chemotherapy Regimen
The intensity of specific chemotherapy regimens is one of the primary determinants of the risk for CIN, with some regimens being more myelosuppressive than others [29]. High cyclophosphamide doses or the use of etoposide (Etopophos^®, VePesid^®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) in treating patients with NHL [16,18] and high anthracycline doses in treating patients with ESBC [24,26] have all been identified as significant predictors for severe neutropenia and FN. High chemotherapy dose intensity has also been identified as a risk factor for neutropenia and its complications in older patients with NHL [19, 20, 22, 26].

CSF Use
Five studies in lymphoma have shown that prophylactically administered CSF is associated with a significantly lower risk of severe neutropenia and FN [16, 18, 20–21].

Predictors of Neutropenic Complications in Children
Most of the studies summarized above were in adult patients with cancer, but predictors of neutropenic complications have also been found in pediatric patients with acute lymphoblastic leukemia and solid tumors (Table 4 and Table 5) [39,40]. In pediatric patients, higher temperature, prolonged neutropenia, a low monocyte count, and shock predicted the occurrence of bacteremia [39, 40, 42].

	RISK FACTORS FOR CIN AND GUIDELINES FOR CSF USE

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Several of the risk factors identified in this study have been incorporated into current guidelines for CSF use. For example, the 2000 update of the American Society of Clinical Oncology (ASCO) guidelines recommended that CSF be initiated in the first cycle in patients at high risk for FN due to special circumstances, such as patients with poor performance status scores, marrow compromise, advanced cancer, overall immune deficit, or active ongoing infections [1]. The greater risk for CIN in older patients was also acknowledged by the Senior Adult Oncology Panel of the National Comprehensive Cancer Network (NCCN) and the Elderly Task Force of the European Organization for Research and Treatment of Cancer (EORTC). Both organizations recommend that prophylactic CSF be used in patients 65 years of age (EORTC defines elderly patients as 60 years) and in patients with lymphoma who are treated with CHOP or CHOP-like chemotherapy [46,47].

	RISK MODELS VERSUS RISK FACTORS

Top Abstract Introduction Risk Factors for CIN Risk Factors for CIN... Risk Models Versus Risk... Conditional Versus Unconditional... Validation of Risk Models Limitations of Current Risk... Risk Models Developed from... Conclusions Disclosure of Potential... References ADDITIONAL READING

 
Studies of individual risk factors for neutropenia and its complications, including reduced RDI, provide useful information for identifying patients at greater risk. However, multivariate risk models capable of considering several independent risk factors are a more powerful method for identifying patients at greater risk for these events. In an analysis of data on 577 patients with intermediate-grade NHL, six independently significant risk factors for FN were identified: age 65 years, renal disease, cardiovascular disease, pretreatment hemoglobin level <12 g/dl, a planned average RDI 80%, and no CSF prophylaxis [19]. Risk scores were calculated for each patient based on the number of risk factors. The risk of FN was found to be lower in patients who had fewer than three risk factors than in patients who had three or more, with the greatest risk occurring in the first cycle of chemotherapy (Fig. 2) [19].

View larger version (17K): [in this window] [in a new window]   Figure 2. Cumulative probability of febrile neutropenia, by number of risk factors.

	CONDITIONAL VERSUS UNCONDITIONAL MODELS

Top Abstract Introduction Risk Factors for CIN Risk Factors for CIN... Risk Models Versus Risk... Conditional Versus Unconditional... Validation of Risk Models Limitations of Current Risk... Risk Models Developed from... Conclusions Disclosure of Potential... References ADDITIONAL READING

View larger version (12K): [in this window] [in a new window]   Figure 3. Risk of first episode of febrile neutropenia in patients with non-Hodgkin’s lymphoma treated with CHOP chemotherapy.

	VALIDATION OF RISK MODELS

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	LIMITATIONS OF CURRENT RISK MODELS

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The clinical prediction models that have been developed to date have been based on retrospective data with many important methodologic limitations [15]. As summarized in Table 7, a good clinical model should minimize bias by clearly stating the hypothesis or purpose in advance, including any subgroup analysis; clearly defining the study population, with specific inclusion and exclusion criteria; and limiting missing data. Models should also be validated in a different set of patients from those in which they were developed. The studies reviewed here are all retrospective in nature, and most have not been designed to test a well-defined hypothesis. They have also been conducted in relatively small study populations and have considered and adjusted for different variables. Furthermore, most models have not been independently validated, and of those models that have been tested in an independent population, only the conditional models are reliable in their predictive power [18, 25, 27, 29].

	RISK MODELS DEVELOPED FROM A PROSPECTIVE REGISTRY

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This registry should thus make it possible to develop more accurate risk models that can eventually be incorporated into actual clinical practice. Such models should facilitate the targeted application of supportive care measures toward patients at greatest risk and most likely to benefit, therefore reducing the risk of neutropenic events, improving treatment outcomes, and reducing health care costs.

	CONCLUSIONS

Top Abstract Introduction Risk Factors for CIN Risk Factors for CIN... Risk Models Versus Risk... Conditional Versus Unconditional... Validation of Risk Models Limitations of Current Risk... Risk Models Developed from... Conclusions Disclosure of Potential... References ADDITIONAL READING

 
Many risk factors for CIN and its serious medical complications have been identified, and several risk models have been developed. The multivariate risk models discussed here have identified advanced age, poor performance status, comorbidities, and low baseline blood cell counts, along with high chemotherapy dose intensity, as significant predictors for neutropenic complications including FN and RDI. Independent risk factors for adverse consequences of neutropenia, including serious medical complications or death, include advanced age, hematologic malignancies, high temperature and low blood pressure on admission, pneumonia, and i.v. site infection, as well as low blood cell counts and evidence of organ dysfunction. The use of such risk factors to identify the patients who are at greatest risk for neutropenia, and targeting prophylactic CSF to those patients, should help providers focus resources on those who are most at risk. The utility of these models is limited, however, by their retrospective design, the small populations studied, and the various risk factors and methods used. To overcome these limitations, we have designed a prospective registry in different tumor types, which should make it possible to develop accurate and valid risk models for CIN and its complications.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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G. Lyman is on the Speaker’s Bureau for Ortho Biotech and Amgen and receives research funding from Amgen, GlaxoSmithKlein, and Genomic Health. The ANC Study Group receives research support from Amgen.

	REFERENCES

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	ADDITIONAL READING

Top Abstract Introduction Risk Factors for CIN Risk Factors for CIN... Risk Models Versus Risk... Conditional Versus Unconditional... Validation of Risk Models Limitations of Current Risk... Risk Models Developed from... Conclusions Disclosure of Potential... References ADDITIONAL READING

Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer 2004;100:228–237.[CrossRef][Medline]

Lyman GH. Risk assessment in oncology clinical practice. From risk factors to risk models. Oncology (Huntingt) 2003;17(suppl 11):8–13.

Lyman GH, Dale DC, Crawford J. Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: a nationwide study of community practices. J Clin Oncol 2003;21:4524–4531.

Lyman GH, Dale DC, Friedberg J et al. Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study. J Clin Oncol 2004;22:4302–4311.

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.[Medline]

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