Incidence of Chemotherapy-Induced Fever and Neutropenia in Different Chemotherapy Regimens in Hospitalized Patients with Non-Metastatic Breast Cancer

² Cancer Prevention Research Center, Deputy for Research & Technology, Isfahan University of Medical Sciences, Isfahan, Iran

*Corresponding author: Arash Ahmadi, Department of Internal Medicine, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran. Email: ahmadi.arash1991@yahoo.com

EXTENDED ABSTRACT

Background

Breast cancer is a major malignancy in women and is the most commonly diagnosed cancer among women worldwide; it is also the leading female cancer in Iran according to the sources cited by the authors [1–3]. Chemotherapy remains an important component of treatment and can reduce cancer-related mortality, but because cytotoxic agents affect dividing cells, treatment may be accompanied by clinically important toxicities including immunosuppression, gastrointestinal mucositis, hepatic dysfunction, dermatitis, alopecia, and hematologic complications [4–6]. Chemotherapy-induced neutropenia (CIN) is one of the common and potentially dose-limiting adverse effects of systemic chemotherapy [7]. Febrile neutropenia (FN) is particularly important because it is an oncologic emergency that may interrupt treatment, require hospitalization, and compromise quality of life or clinical outcomes [8–10]. Granulocyte colony-stimulating factor (G-CSF) is used to stimulate neutrophil production and is recommended as primary prophylaxis when the expected risk of FN is sufficiently high and as secondary prophylaxis in selected patients who have already experienced a neutropenic complication [11–14]. Previous studies cited in the article have identified several potential risk factors for CIN or FN, including older age, impaired performance status, bone metastasis, inflammatory or autoimmune disease, low pretreatment blood indices, low albumin, and anthracycline-taxane combination therapy [15–17]. However, local information on the occurrence and risk profile of CIN and FN among Iranian patients with breast cancer has been limited. The present study therefore evaluated the incidence of chemotherapy-induced neutropenia and febrile neutropenia across commonly used chemotherapy regimens in hospitalized patients with non-metastatic breast cancer and examined their associations with selected clinical characteristics.

Methods

This retrospective descriptive cross-sectional study included 200 adult women with pathologically confirmed non-metastatic breast cancer who had been hospitalized at Seyed al-Shohada (Omid) Hospital in Isfahan and treated between 2016 and 2021. Patients were identified by census sampling from those receiving one of three chemotherapy regimens: AC, AC-T, or TAXANE. Data were extracted from the hospital breast-cancer registry and hospital information system and recorded in a study checklist. Variables included age, underlying diseases, pathologic findings, tumor stage, chemotherapy regimen, number and timing of adjuvant or neoadjuvant chemotherapy sessions, occurrence of fever after chemotherapy, absolute blood-cell counts, and administration of G-CSF. Patients were eligible if they were older than 18 years, had breast cancer confirmed by pathology, and had received one of the specified chemotherapy regimens. Patients with uncontrolled infectious disease such as hepatitis or HIV, those receiving radiotherapy or hormonal treatment, and those with incomplete medical records for required study variables were excluded. Neutropenia was defined on the basis of absolute neutrophil count (ANC) and was graded according to the Common Terminology Criteria for Adverse Events version 5 as mild (ANC 1.0-1.5×10^9/L), moderate (0.5-1.0×10^9/L), severe (0.2-0.5×10^9/L), and very severe/agranulocytosis (<0.2×10^9/L) [18]. Febrile neutropenia was defined as ANC <1000/mm3 together with a single temperature >38.3°C or a sustained temperature ≥38.0°C for more than 1 hour. The investigators also recorded whether G-CSF had been administered after recognition of neutropenia or FN and explored its relationship with these outcomes. Data were analyzed with SPSS. Descriptive statistics were reported as means, standard deviations, counts, and percentages. Chi-square or Fisher exact tests were used for categorical comparisons and t tests for continuous variables, with P<0.05 considered statistically significant. The study received research-ethics approval from Isfahan University of Medical Sciences (IR.MUI.REC.1402.035).

Results

The mean age of the 200 patients was 46.90±11.28 years (range, 18-86 years). Thirty patients had hypertension and 17 had diabetes. With respect to chemotherapy regimen, 55 patients (27.5%) received AC, 117 (58.5%) received AC-T, and 28 (14.0%) received TAXANE. Twenty-five patients (12.5%) received G-CSF. Overall, 31 patients developed chemotherapy-induced neutropenia, corresponding to an incidence of 15.5%, and 19 developed febrile neutropenia, corresponding to an incidence of 9.5%. Among patients with neutropenia, 54.8% of cases were mild, 35.5% were moderate, and 9.7% were severe. The frequency of neutropenia was 21.8% with AC, 13.7% with AC-T, and 10.7% with TAXANE (P=0.327). Febrile neutropenia occurred in 7.1%, 9.4%, and 7.1% of patients receiving AC, AC-T, and TAXANE, respectively (P=0.889). Neutropenia severity also did not differ significantly by chemotherapy regimen (P=0.225). Thus, the regimen itself was not statistically associated with CIN, neutropenia severity, or FN in this cohort. Cancer stage showed a significant relationship with neutropenia. No patient with stage 1 disease developed neutropenia; the frequencies were 12.0% in stage 2 and 37.5% in stage 3 disease (P=0.006). A similar gradient was reported for febrile neutropenia: 0% in stage 1, 5.4% in stage 2, and 32.3% in stage 3 disease (P<0.001). Neutropenia occurred in 100% of patients who had received G-CSF versus 3.4% of those who had not (P<0.001), while FN occurred in 60.0% versus 2.3%, respectively (P<0.001). The authors emphasized that this association should not be interpreted as a harmful effect of G-CSF because, in routine practice represented by the records, G-CSF was commonly prescribed after neutropenia or FN had already occurred rather than consistently as primary prophylaxis. Hypertension was associated with a higher frequency of CIN (30.0% vs 12.9%; P=0.027) and FN (20.0% vs 7.6%; P<0.05), whereas diabetes was not significantly associated with either CIN (P=0.308) or FN (P=0.209). Age was also associated with both outcomes. Patients with CIN were older than those without CIN (51.93±12.86 vs 45.98±10.75 years; P=0.007), and patients with FN were older than those without FN (52.52±15.07 vs 46.31±10.69 years; P=0.022). These findings identified older age, higher tumor stage, and hypertension as clinical characteristics associated with greater occurrence of neutropenic complications in the study population, while no significant relationship was demonstrated with the type of chemotherapy regimen or diabetes.

Table 1. Frequency of neutropenia, neutropenia severity, and febrile neutropenia according to chemotherapy regimen.

Table 2. Frequency of chemotherapy-induced neutropenia according to cancer stage, G-CSF administration, hypertension, and diabetes.

Figure 2. Mean age of patients according to occurrence of chemotherapy-induced neutropenia and febrile neutropenia.

Conclusion

Chemotherapy-induced neutropenia and febrile neutropenia were relatively common complications among hospitalized women with non-metastatic breast cancer receiving AC, AC-T, or TAXANE regimens, with observed incidences of 15.5% and 9.5%, respectively. The study did not identify a significant difference in neutropenia or FN across the three chemotherapy regimens. In contrast, older age, more advanced tumor stage, and hypertension were associated with higher frequencies of these complications. The apparent association with G-CSF reflected the retrospective treatment pattern in which G-CSF was frequently administered after a neutropenic event and therefore should not be interpreted as evidence that G-CSF caused neutropenia. The findings support careful identification of patients with clinical risk factors and appropriate use of preventive strategies. Because the study was retrospective, relied on records from a single center, and was limited by incomplete documentation for some variables, causal inference and generalization should remain cautious.

Keywords: Breast Neoplasms, Drug Therapy, Fever, Neutropenia

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