Abstract
Chemotherapy-induced neutropenia is a common adverse effect, with severe neutropenia associated with significant morbidity, mortality, and costs that require immediate evaluation and treatment. To identify the risk factors that may predispose adult patients with solid cancers to severe intravenous chemotherapy-induced neutropenia, we conducted a retrospective study. A study was performed by collecting data of solid cancer patients who received intravenous chemotherapy from January 2023 to May 2024 at Shanghai Sixth People’s Hospital Affiliated to Shanghai JiaoTong University, South Campus. Patient data including age, sex, body mass index, Eastern Cooperative Oncology Group (ECOG) performance status, number of chemotherapy lines, number of chemotherapy drugs, radiotherapy history, and comorbidities were collected. We analyzed potential risk factors for severe neutropenia. In total, 343 patients were included in the analysis. Multivariate analysis showed that female sex (odds ratio [OR] 1.84; 95% confidence interval [CI] 1.06–3.18; P < .03), number of chemotherapy lines (OR 1.51; 95% CI 1.06–2.13; P < .02), and radiotherapy history (OR 2.53; 95% CI 1.04–6.19; P < .04) were independent predictors of severe neutropenia. Comorbidity (OR, 0.46; 95% CI 0.26–0.81; P < .007) was found to be an independent predictor of no severe neutropenia. In conclusion, we found that female sex, a larger number of chemotherapy lines, and a history of radiotherapy might be predictors of severe neutropenia. Comorbidity may be a protective factor against severe neutropenia.
Keywords: Intravenous chemotherapy, risk factor, severe neutropenia, solid cancer
1. Introduction
Chemotherapy is widely used as the standard treatment for most cancers, with the primary goals of prolonging survival, alleviating or preventing tumor-related symptoms or consequences, and improving the quality of life. However, chemotherapy may cause significant toxicities that result in various symptoms, including vomiting, hair loss, mucositis, neutropenia, fatigue, nausea, diarrhea, and neuropathy. Among these side effects, chemotherapy-induced neutropenia is a crucial dose-limiting factor of myelo-suppressive chemotherapy, which often leads to chemotherapy reductions or treatment delays in subsequent cycles and potentially compromises treatment outcomes.[1–3]
Chemotherapy is a common treatment for cancer; however, it carries the risk of neutropenic complications, making it difficult for clinicians to predict whether a patient is at a higher risk.[4] Severe neutropenia is defined as an absolute neutrophil count (ANC) of <500 cells/µL of blood, which may increase the risk of life-threatening infections. Severe chemotherapy-induced neutropenia is a common and serious side effect of chemotherapy. Febrile Neutropenia (FN), considered as an oncologic emergency, is defined by the Infectious Diseases Society of America, American Society of Clinical Oncology (ASCO), and National Comprehensive Cancer Network (NCCN) as an oral temperature ≥ 38.3°C (101.0°F), or a sustained temperature ≥ 38.0°C (100.4°F) for 1 hour, and an ANC < 0.5 × 109/L or an ANC expected to decrease to < 0.5 × 109/L within 48 hours.[5–7] The international guidelines recommend primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) when the risk of febrile neutropenia (FN) is > 20%.[8] Identifying the risk factors for chemotherapy-induced neutropenia (CIN) is helpful for appropriately targeting CSF prophylaxis, preventing complications, and increasing mortality in patients.[9] Severe neutropenia is the most serious form of neutropenia, with or without fever. Identifying the risk factors for chemotherapy-induced severe neutropenia has much more significance, such as eliminating unnecessary dose reductions, reducing treatment delays, and unnecessary use of antibiotics and G-CSF.
Currently, some retrospective analyses have evaluated whether particular patient factors increase the risk of CIN and FN, but not chemotherapy-induced severe neutropenia. Therefore, this study aimed to identify shared factors among patients that may predict a higher propensity to develop chemotherapy-induced severe neutropenia. By identifying these risk factors, healthcare providers can take appropriate measures to prevent and manage chemotherapy-induced severe neutropenia, ultimately improving treatment outcomes and quality of life.
2. Patients and methods
This retrospective, observational study was conducted in the Department of Medical Oncology at a tertiary care hospital. Patients had their neutrophil counts checked every 3 days after chemotherapy. Eligibility criteria included patients aged at least 18 years with a primary solid cancer who had received intravenous chemotherapy at least once between January 2023 and May 2024. The exclusion criteria were as follows: pregnancy, neutrophil count below the lower limit of normal at baseline, and use of G-CSF for primary or secondary prophylaxis or therapeutic purposes. Data were collected through direct examination of the patients’ medical records. The requirement for patient consent was waived, because this was a retrospective data analysis, without any direct interaction with the patients.
The objective of this study was to identify the risk factors predictive of chemotherapy-induced severe neutropenia, a serious adverse effect defined as an absolute neutrophil count (ANC) of <500 cells/µL of blood. Patients were divided into two cohorts in order to assess the risk factors associated with the occurrence of severe neutropenia: those with severe neutropenia and those without severe neutropenia.
Patient information, including age, sex, body mass index, Eastern Cooperative Oncology Group (ECOG) performance status, number of chemotherapy lines, number of chemotherapy drugs, radiotherapy history, and comorbidities were collected. Body mass index was categorized into discrete categories using the CDC recommended guidelines: underweight (< 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), and obese (≥ 30 kg/m2).[10] Before chemotherapy, the patients’ physical condition was assessed based on the ECOG scoring criteria. It is a clinician-assessed scale from 0 to 5 that evaluates a patient’s functional ability, where 0 indicates full activity without any restrictions, 1 signifies restricted strenuous activity but capability for light work, 2 indicates ambulatory capacity and self-care but inability to work, 3 indicates limited self-care and confinement to a bed or chair for over half of waking hours, 4 indicates complete disability and total confinement, and 5 indicates death. Postoperative adjuvant chemotherapy was defined as 0 lines. 1, 2, 3, and 4 were defined as the corresponding numbers of palliative chemotherapy lines. Comorbidities were defined as non-chemotherapy-induced disease states.
Continuous data are presented as median and range. The Mann-Whitney U-test was used to compare data with medians. The chi-square test and Fisher’s exact test were used to analyze nominal scales. Multiple logistic regression analysis was conducted for factors that were significant in univariate logistic regression analysis. All statistical analyses were considered to be statistically significant at P < .05. Statistical analyses were performed using Statistical Package for the Social Sciences (version 23.0; IBM Co., Armonk, NY, USA). This study was approved by the Ethics Committee of Shanghai Sixth People’s Hospital, South Campus, Shanghai JiaoTong University.
3. Results
The study population consisted of 343 patients with solid cancers who received intravenous chemotherapy between January 2023 and May 2024. The primary cancers were colorectal cancer (116, 33.8%), gastric cancer (64, 18.7%), and lung cancer (26, 7.6%). Colorectal and gastric cancer patients (180, 52.5%) accounted for more than half of the patients. Most patients received oxaliplatin and fluorouracil chemotherapy. The second largest number of patients were those with lung cancer. They mostly received paclitaxel, gemcitabine, or pemetrexed combined with cisplatin or carboplatin. A total of 197 patients (57.4%) were male. The median age of the patients was 56 years (range 20–82 years). A total of 307 (89.5%) patients had an ECOG score of 0 or 1. A total of 122 (35.6%) patients received postoperative adjuvant chemotherapy, and the rest received advanced rescue chemotherapy. Generally, the greater the number of lines of chemotherapy a patient receives, the greater the tumor burden. The median number of chemotherapy lines for all patients was one (range 0–4). The patients received a median of two chemotherapy drugs. Only 25 patients (7.3%) received radiotherapy. A total of 175 (51.0%) patients had comorbidities, including 159 (90.9%) with hypertension, diabetes, coronary heart disease, or arrhythmia and 4 patients with renal insufficiency. The total study population was unevenly distributed in BMI categories, with 13.4% underweight, 66.4% normal, 18.9% overweight, and 1.1% obese. Overall, 74 patients (21.6%) experienced severe neutropenia.
Analysis of our data revealed a significant correlation between severe neutropenia and patient-specific characteristics, such as patient sex. Using the Pearson Chi-square test, we found that chemotherapy-induced severe neutropenia was associated with female sex (P < .024).
There was a significant correlation between chemotherapy-induced severe neutropenia and an ECOG score of 1 or 2 (P < .038). Severe neutropenia was also associated with more chemotherapy lines (P < .003), a history of radiotherapy (P < .005), and fewer comorbidities (P < .005). The clinical characteristics related to the risk of severe neutropenia are shown in Table 1.
Table 1.
Association between severe neutropenia and patient, ECOG performance score, number of chemotherapy lines and chemotherapy drugs, radiotherapy history, comorbidity.
| No severe neutropenia (n = 269) | Severe neutropenia (n = 74) | p-value | |
|---|---|---|---|
| Age (years), median (range) | 57 (20–82) | 53 (21–80) | .611* |
| Sex, female, n(%) | 106 (39.4%) | 40 (54.1%) | .024‡ |
| BMI (kg/m2), median (range) | 22.0 (14.2–33.8) | 21.5 (17.5-29.3) | .437* |
| BMI group | 1.000† | ||
| Underweight (< 18.5 kg/m2) | 38 (14.1%) | 7 (9.5%) | |
| Normal (18.5–24.9 kg/m2) | 169 (62.8%) | 56 (75.7%) | |
| Overweight (25–29.9kg/m2) | 58 (21.6%) | 11 (14.9%) | |
| Obese (≥ 30 kg/m2) | 4 (1.5%) | 0 | |
| ECOG performance score (points) | .038‡ | ||
| 0 | 111 (41.3%) | 19 (25.7%) | |
| 1 | 133 (49.4%) | 44 (59.5%) | |
| 2 | 25 (9.3%) | 11 (14.9%) | |
| Number of chemotherapy lines, median (range) | 1 (0–4) | 1 (0–4) | .003* |
| Number of chemotherapy drugs, median (range) | 2 (1–3) | 2 (1–3) | .229* |
| Radiotherapy history | 14 (5.2%) | 11 (14.9%) | .005‡ |
| Comorbidity, n(%) | 148 (55.0%) | 27 (36.4%) | .005‡ |
BMI = body mass index, ECOG = Eastern Cooperative Oncology Group.
Mann-Whitney U test.
Fisher’s exact test.
chi-square test.
By univariate analysis (Table 2), female gender (odds ratio [OR] 1.81; 95% confidence interval [CI] 1.08–3.04;P < .025), ECOG performance score (OR 1.67; 95% CI 1.12–2.50; P < .013), number of chemotherapy lines (OR 1.79; 95% CI 1.33–2.42; P < .001), and radiotherapy history (OR 3.18; 95% CI 1.38–7.34; P < .007) were associated with an increased risk of severe neutropenia occurrence. Comorbidity (OR, 0.47; 95% CI 0.28–0.80; P < .005) was associated with a reduced risk of severe neutropenia. Age, body mass index, and number of chemotherapy drugs were not associated with an increased risk of severe neutropenia.
Table 2.
Univariable analysis of risk factors for developing chemotherapy-induced grade 4 neutropenia.
| OR | 95%CI | p-value | |
|---|---|---|---|
| Age | |||
| >=65 vs <65 | 1.18 | 0.71–1.98 | 0.52 |
| Sex | |||
| Female vs male | 1.81 | 1.08–3.04 | 0.025 |
| BMI category | 0.92 | 0.60–1.41 | 0.69 |
| ECOG performance score | 1.67 | 1.12–2.50 | 0.013 |
| Number of chemotherapy lines | 1.79 | 1.33–2.42 | <0.001 |
| Number of chemotherapy drugs | 0.92 | 0.44–1.92 | 0.82 |
| Radiotherapy history | |||
| Yes vs no | 3.18 | 1.38–7.34 | 0.007 |
| Comorbidity | |||
| Yes vs no | 0.47 | 0.28–0.80 | 0.005 |
BMI = body mass index, CI = confidence interval, ECOG = Eastern Cooperative Oncology Group, OR = odds ratio.
The multivariable analysis assessed the risk of severe neutropenia, controlling for sex, ECOG performance score, number of chemotherapy lines, radiotherapy history, and comorbidity (Table 3). After controlling for other variables, female sex (OR 1.84; 95% CI 1.06–3.18; P < .03), number of chemotherapy lines (OR 1.51; 95% CI 1.06–2.13; P < .02), and radiotherapy history (OR 2.53; 95% CI 1.04–6.19; P < .04) were found to be independent predictors of severe neutropenia. Comorbidity (OR, 0.46; 95% CI 0.26–0.81; P < .007) was also found to be an independent predictor of severe neutropenia.
Table 3.
Multivariable analysis of risk factors for developing severe neutropenia.
| OR | 95%CI | p-value | |
|---|---|---|---|
| Sex | |||
| Female vs male | 1.84 | 1.06–3.18 | 0.03 |
| ECOG performance score | 1.39 | 0.86–2.23 | 0.18 |
| Number of chemotherapy lines | 1.51 | 1.06–2.13 | 0.02 |
| Radiotherapy history | |||
| Yes vs no | 2.53 | 1.04–6.19 | 0.04 |
| Comorbidity | |||
| Yes vs no | 0.46 | 0.26–0.81 | 0.007 |
CI = confidence interval, ECOG = Eastern Cooperative Oncology Group, OR = odds ratio.
4. Discussion
Our results indicate that female sex, a large number of chemotherapy lines, and a history of radiotherapy were associated with the occurrence of severe neutropenia. Comorbidities are associated with a reduced risk of severe neutropenia.
Female patients are more likely to experience severe neutropenia after chemotherapy, the mechanism of which is unclear and deserves further investigation.
Chemotherapy can damage the bone marrow. The more lines of chemotherapy a patient receives, the more severe the bone marrow damage. This is consistent with our results, which showed that patients with a larger number of chemotherapy lines were at a higher risk of developing severe neutropenia. In a study investigating the risk factors for chemotherapy-induced neutropenia, multiple lines of chemotherapy were suggested to be a risk factor for neutropenia development.[11] These findings highlight the importance of early monitoring of severe neutropenia in patients who have received multiple lines of chemotherapy.
Radiotherapy can also damage the patient’s bone marrow and affect the hematopoietic capacity. Our results confirmed this theory.
Patients with comorbidities had a reduced risk of developing severe neutropenia. This seems to contradict the findings of previous studies. A study conducted in an Indian population found that diabetes mellitus increased the risk of chemotherapy-induced neutropenia.[12] The comorbidity of heart disease increases the risk of neutropenia or FN.[13] A cohort study conducted in Kaiser Permanente Southern California, a large managed care organization, found that several chronic comorbidities increase the risk of chemotherapy-induced FN.[14] A retrospective study by Sophie et al found that the presence of multiple comorbidities increased the risk of FN in patients receiving docetaxel for mCRPC.[15] The presence of two or more comorbidities is significantly associated with FN.[16] Our findings suggest that comorbidities are a significant protective factor against severe neutropenia. A possible reason might be that patients with comorbidities are more likely to seek medical attention and receive timely detection and prompt treatment of neutropenia, thus preventing the occurrence of severe neutropenia. However, further research is needed to confirm these findings and explore the underlying mechanisms.
Identifying risk factors for chemotherapy-induced severe neutropenia can provide several benefits. First, it can help healthcare professionals better predict and prevent the occurrence of severe neutropenia in patients undergoing chemotherapy. This will reduce the incidence of infections and other complications associated with severe neutropenia, ultimately improving treatment outcomes and the quality of life of patients. Second, identifying the risk factors for severe neutropenia can help inform treatment decisions, such as the choice of chemotherapy regimen or the use of prophylactic measures to prevent severe neutropenia. This will provide personalized and effective treatment plans for patients, thereby improving their overall treatment experience. Finally, understanding the risk factors for chemotherapy-induced severe neutropenia can inform future research and the development of new therapies or interventions to prevent or manage severe neutropenia in patients with cancer.
Our study had several limitations. The major disadvantages were the retrospective nature of the study and the fact that we provided only a single-center experience. It is important to conduct multicenter studies with a wide range of patient diversity to confirm our results. In addition, because the study was conducted by querying electronic medical records, there is a possibility of selection bias. Another point that must be mentioned is that our study lacked external validation.
5. Conclusion
In conclusion, we found that female sex, a large number of chemotherapy lines, and a history of radiotherapy might be predictors of the occurrence of severe neutropenia. Comorbidity may be a protective factor against severe neutropenia.
Author contributions
Conceptualization: Na Zhang.
Methodology: Na Zhang.
Writing – original draft: Na Zhang.
Writing – review & editing: Aina He.
Abbreviations:
- ANC
- absolute neutrophil count
- ASCO
- American Society of Clinical Oncology
- BMI
- body mass index
- CDC
- Centers for Disease Control
- CI
- confidence interval
- CIN
- chemotherapy-induced neutropenia
- ECOG
- Eastern Cooperative Oncology Group
- FN
- febrile neutropenia
- G-CSF
- Granulocyte Colony-Stimulating Factor
- NCCN
- National Comprehensive Cancer Network
- OR
- odds ratio
The Ethics Review Committee of the Shanghai Fengxian District Central Hospital approved this study.
The authors have no funding and conflicts of interest to declare.
The datasets generated during and/or analyzed during the current study are publicly available.
How to cite this article: Zhang N, He A. Search for risks of intravenous chemotherapy-induced severe neutropenia in solid cancers: A retrospective observational study. Medicine 2026;105:36(e50514).
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