Risk Factors for Chemotherapy Induced Febrile Neutropenia

Infection and inflammation stimulate release of endogenous cytokines (e.g., inter-leukin-1 [IL-1], tumor necrosis factor [TNF], and IL-6) into the circulation. These cytokines reset the thermoregulatory center in the hypothalamus to retain heat and allow the core temperature of the body to increase. Mononuclear phagocytes are the principle producers of the endogenous cytokines that cause fever and are much less affected by chemotherapy than neutrophils. Therefore, fever is reliable as a marker of infection in patients receiving chemotherapy, including neutropenic patients.

Over the past decade, the risk of FN among patients receiving cancer therapy has received increasing attention. In 1992, Talcott and colleagues (4) studied 444 patients with cancer who had fever and neutropenia and were hospitalized. Clinical parameters that predicted subsequent morbidity and mortality and were easily measurable during the first 24 h of hospitalization were identified. The presence of serious comorbidities or uncontrolled cancer or the development of FN during hospitalization predicted an adverse outcome. The in-hospital mortality rate was approx 10% for patients with one of these identified risk factors. This study also identified patients with a low morbidity and mortality risk that could be managed with shorter hospitalizations and less intensive antibiotic treatments.

In a review of the risk of FN among patients with intermediate-grade NHL receiving cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy, Lyman and coworkers (5,6) identified several factors associated with an increased risk of neu-tropenia-related complications. Data for this study came from 577 patients and 224 occurrences of FN in 12 community and academic oncology practices. Age > 65 yr (p = 0.001), significant cardiovascular or renal disease (p = 0.02), baseline hemoglobin concentration < 12 g/dL (p = 0.018), and administration of >80% planned dose intensity (p = 0.018) were associated with an increased risk of neutropenia-related complications. In this study, patients not receiving prophylactic colony-stimulating factor (CSF) had a significantly greater risk of FN (p = 0.046) than patients receiving prophylactic CSF. In multivariate analysis, the risk of FN remained significant for age, cardiovascular and renal disease, baseline hemoglobin concentration, planned chemotherapy dose, and no CSF prophylactic treatment. No significant relationship among sex, stage of disease at initiation of therapy, or lactic dehydrogenase value was reported.

Another predictive model is based on measurement of neutrophil counts before and after the first course of chemotherapy. Silber and coworkers (7) first reported this model to predict FN in patients with early-stage breast cancer receiving adjuvant chemotherapy. This study and subsequent investigations (8) showed that patients with an ANC < 0.5 x 109/L during the first chemotherapy cycle are at increased risk of serious neutropenia-related adverse effects during subsequent chemotherapy cycles. This important finding led to the practice of secondary prophylaxis (i.e., giving growth factors, specifically rHuG-CSF, only to patients shown to be at high risk for severe neu-tropenia based on neutrophil data from their first cycle of treatment).

Further investigations, however, have revealed that elderly patients, and perhaps some other groups, are at high risk of FN during their first course of chemotherapy. In reviewing CHOP therapy for NHL, Lyman et al. (6) found that 74% of all FN episodes occurred with the first two cycles of chemotherapy. For patients > 65 yr of age, the incidence of first-cycle FN was about 20%, with a gradual increase in the cumulative probability of FN over the course of treatment to approx 35%. Thus, >50% of these events occurred with the first exposure to chemotherapy. In a parallel investigation of the risk of FN in patients with breast cancer receiving adjuvant therapy, Agboola and cowork-ers (9) reported that increasing age predicted hematologic toxicity. In this report, other predictors were an ANC < 0.5 x 109/L and a first-cycle decrease in hemoglobin concentration > 1 g/dL. In addition, FN during the first chemotherapy cycle predicted FN during subsequent cycles.

An important and provocative finding in these investigations is the high proportion of overall risk of FN that is present at the beginning of treatment, which is when standard-dose chemotherapy is first given to a previously untreated patient. For years, the treatment paradigm has emphasized the progressive toxicity associated with sequential chemotherapy dosing. Direct and predictable cumulative toxicity for erythroid cells and platelets may occur, but current data suggest that myeloid cells (i.e., neutrophils and monocytes) may show inherently different responses. Careful observation of blood cell counts in patients with small-cell lung cancer (SCLC) treated with up to six cycles of cyclophosphamide, doxorubicin, and etoposide illustrated that neutrophil counts were not progressively lower with each cycle (10). These results suggest that the hematopoietic tissues of the bone marrow adapt to the sequential insults of chemotherapy, just as the bone marrow adapts to produce more neutrophils in response to chronic infection. This study also illustrated the effects of rHuG-CSF treatment, which ameliorated the effects of chemotherapy, reducing the depth and duration of neutropenia.

As these studies point out, age is a consistent predictor of FN risk. It is known that blood cell counts, including neutrophil and monocyte counts, are similar in healthy young and healthy elderly patients. The functions of these cells are similar in healthy young and healthy elderly patients. Some evidence points to a decrease in the hematopoietic reserves in the elderly, as reflected by reduced numbers of CD 34+ hematopoietic progenitor cells mobilized after stimulation with rHuG-CSF (11). Results from a small, but provocative, study of patients with SCLC suggest that a reduced CD 34+ cell response to rHuG-CSF predicts a greater risk of developing neu-tropenia after cancer chemotherapy (12). Thus, CD34+ cell counts may be a better predictor of neutropenia risk than blood neutrophil counts. Further investigation of the number and function of these progenitor cells before and during cancer chemotherapy may be helpful in developing new biologic predictors that could be used to predict patients at risk of developing neutropenia.

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