DOI: https://doi.org/10.21203/rs.3.rs-1588526/v1
Purpose
Chemotherapy-induced febrile neutropenia (FN) is a medical emergency that can cause severe adverse effects and death. Respiratory infection is one of the main causes of FN. We studied whether infection prevention and control (IPC) guidance for COVID-19 reduces the incidence of FN.
Methods
We reviewed female breast cancer patients treated with adjuvant docetaxel, doxorubicin, and cyclophosphamide (TAC) with prophylactic pegfilgrastim between 2019 and 2021. IPC guidance has been implemented since April 2020.
Results
There was no difference in the incidence of chemotherapy-induced neutropenia (CIN) between patients without and with IPC. In the IPC patients, the incidence of FN (9.5%), hospitalization duration (0.7 ± 1.5 days), and total hospital cost (279.6 ± 42.6 USD) were significantly lower than in non-IPC patients (27.9%, 2.0 ± 3.8 days and 364.7 ± 271.6 USD, respectively).
Conclusion
IPC guidance should be implemented to prevent FN in high-risk patients.
Breast cancer is a systemic disease, and many breast cancer patients need chemotherapy in addition to oncological surgery and radiotherapy.[1] Dose-dense anthracycline/taxane- and docetaxel-based regimens are often used in breast cancer. According to international guidelines, the docetaxel, doxorubicin, and cyclophosphamide (TAC) regimen carries a high risk (> 20%) of chemotherapy-induced neutropenia (CIN) and its complications.[2, 3]
Patients with CIN may progress to febrile neutropenia (FN), which is a serious medical problem. TAC causes significantly more hematological adverse effects than other breast cancer chemotherapy regimens.[4] The use of prophylactic pegfilgrastim significantly reduced the incidence of CIN and FN in patients receiving TAC chemotherapy, although the rates were still high at 74–91.4% and 7–21.4%, respectively.[5–8]
One of the main causes of fever in CIN patients is respiratory infection.[9] To prevent the spread of COVID-19, mask-wearing and physical distancing have been implemented. We investigated whether this COVID-19 infection prevention and control (IPC) guidance helped reduce the risk of FN in breast cancer patients receiving TAC chemotherapy.
This was a single-center retrospective observational study. The study protocol was approved by the institutional review board of the Catholic University of Korea (VC22RASI0019). Electronic medical records of female breast cancer patients who received adjuvant TAC chemotherapy with prophylactic pegfilgrastim from January 2019 to December 2021, at St. Vincent’s Hospital of the Catholic University of Korea, were reviewed. Patients were excluded if they were pregnant or taking immunosuppressive drugs, had previously received other chemotherapy, had abnormal hematopoietic, liver, renal, or cardiac function before the chemotherapy, or had an Eastern Cooperative Oncology Group (ECOG) score of ≥ 2.
Variables extracted from the database included patient demographics, ECOG performance status, characteristics of the cancer [histological type and grade, stage, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), surgery type, radiation therapy], laboratory results, and infectious diseases. ER and PR status, as determined using enzyme immunoassays, was obtained from the medical records. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or silver in situ hybridization (SISH) was used to evaluate HER2 status. Samples with an IHC score of 0 or + 1, or an IHC score of + 2 and negative FISH/SISH, were considered negative for HER2 overexpression. Data were collected between the start of chemotherapy and 2 months thereafter.
The chemotherapy consisted of doxorubicin (50 mg/m2), cyclophosphamide (500 mg/m2), and docetaxel (75 mg/m2), administered on day 1 (and every 3 weeks thereafter). Pegfilgrastim 0.6 mL was administered subcutaneously 24–48 hours later. Laboratory tests, including complete blood count (CBC) with differential and biochemistry assays, were performed before each chemotherapy cycle and on day 6. After chemotherapy, the CBC was measured from day 6 until the absolute neutrophil count returned to 1,000/mm3. All patients with grade 4 CIN received prophylactic antibiotic therapy comprising 2 g intravenous cefoperazone and 200 mg tobramycin sulfate once daily, unless their use was contraindicated.
ECOG performance status describes a patient’s level of function and self-care capability.[10] It ranges from 0 to 5, with 0 indicating an active person able to carry out all pre-disease activities without restriction, and 5 indicating death. Each patient’s performance status was evaluated before the first chemotherapy cycle. The adverse events of interest were based on the Common Terminology Criteria for Adverse Events (ver. 6.0).
FN was defined as neutropenia (< 500 neutrophils/µL or < 1,000 neutrophils/µL for over 48 hours) with a febrile event (oral temperature ≥ 38.3°C or ≥ 38.0°C for over 1 hour) observed by medical staff. Dose reduction was defined as a reduction in the delivered dose of any agent relative to the standard values. The total hospital cost was the sum of all medical expenses paid to the hospital during the data collection period. Outpatient hospital visit, hospitalization, and chemotherapy costs, and the costs of all devices and drugs used for medical purposes, were included in the total hospital cost.
IPC guidance to prevent COVID-19 infection includes good personal hygiene, prioritizing handwashing, cleaning high-touch surfaces such as mobile phones regularly or as needed, covering the mouth when coughing and sneezing, and wearing masks. Social distancing involves staying at least 2 meters away from others, avoiding poorly ventilated spaces and crowds, and following work and quarantine restrictions.[11] There are three levels of social distancing, implemented according to the number of patients diagnosed with COVID-19.[12] IPC guidance has been implemented since April 2020.
The chi-square test was used to compare categorical variables. Standardized residuals were analyzed for variables with more than two categories. Student’s t-test was used for analyzing continuous variables. To identify independent risk factors for FN, multivariate logistic regression including variables significant in the univariate analyses was performed. The analyses were performed using R software (ver. 4.0.2, R Core Team, 2013).
Of the 85 chemotherapy patients, IPC was applied for 43, but not for the remaining 42. The mean age of the two groups was 53.7 and 52.3 years, respectively (p > 0.05). Significantly more patients in the non-IPC group were ER-positive (72.7% vs. 52.4%). Table 1 summarizes the characteristics of the patients in each group. All included patients had an ECOG score of 0 and none had COVID-19 infection during the follow-up period.
Grade 4 CIN occurred in 93.0% (40/43) of the non-IPC group and 90.5% (38/42) of the IPC group (p = 0.713). FN occurred significantly less often in the IPC group (9.5% vs. 27.9%; p = 0.050). The duration of hospitalization, hospitalization cost, and total hospital cost were significantly lower in the IPC group. There were no significant group differences in adverse effects, including anemia, thrombocytopenia, liver or renal function abnormality, and transfusion. There was also no group difference in the dose reduction or delay of chemotherapy (Table 2). Of the 14 patients who developed FN, 2 (12.5%) died of sepsis during the observation period. All deaths were in the non-IPC group, but there was no statistical difference compared to the IPC group.
The factors that differed significantly between the groups in the univariate logistic regression analysis of FN development were IPC and comorbidities (Table 3). Multivariate logistic regression analysis revealed that both factors were independently associated with an increased likelihood of FN development (odds ratio/95% confidence interval: 4.668/1.238–17.602 and 5.554/1.294–23.843, respectively) (Table 4).
| COVID-19 prevention and control | |||
|---|---|---|---|
| No (n = 43) | Yes (n = 42) | p-value | |
| Age (years) | 52.3 ± 8.3 | 53.7 ± 8.6 | 0.452 |
| BMI (kg/m2) | 24.8 ± 3.6 | 24.7 ± 3.7 | 0.924 |
| BSA (m2) | 1.6 ± 0.1 | 1.6 ± 0.1 | 0.962 |
| Age (years) < 60 ≥ 60 | 33 (76.7) 10 (23.3) | 28 (66.7) 14 (33.3) | 0.342 |
| Type of surgery BCS Mastectomy | 39 (90.7) 4 (9.3) | 41 (97.6) 1 (2.4) | 0.360 |
| T stage I II III, IV | 26 (60.5) 15 (34.9) 2 (4.7) | 16 (38.1) 25 (59.5) 1 (2.4) | 0.074 |
| N stage 0 I II, III | 7 (16.3) 27 (62.8) 9 (20.9) | 9 (21.4) 19 (45.2) 14 (33.3) | 0.257 |
| Histological type IDC ILC Others | 37 (86.0) 2 (4.7) 4 (9.3) | 34 (81.0) 1 (2.4) 7 (16.7) | 0.531 |
| Histologic grade G1, G2 G3 | 28 (65.1) 15 (34.9) | 17 (42.9) 24 (57.1) | 0.051 |
| Estrogen receptor Positive Negative | 33 (76.7) 10 (23.3) | 22 (52.4) 20 (47.6) | 0.024 |
| Progesterone receptor Positive Negative | 18 (41.9) 25 (58.1) | 12 (28.6) 30 (71.4) | 0.258 |
| HER2 Positive Negative | 8 (18.6) 35 (81.4) | 11 (26.2) 31 (73.8) | 0.444 |
| Comorbidity No HTN DM HTN + DM | 38 (88.4) 1 (2.3) 2 (4.7) 2 (4.7) | 35 (83.3) 6 (14.3) 0 (0.0) 1 (2.4) | 0.111 |
| Smoking Yes No | 0 (0) 43 (100) | 1 (2.4) 41 (97.6) | 0.494 |
| Data are expressed as n (%) | |||
| BMI, body mass index; BSA, body surface area; DM, diabetes mellitus, HER2, human epidermal growth factor receptor 2; HTN, hypertension | |||
| COVID-19 prevention and control | |||
|---|---|---|---|
| No (n = 43) | Yes (n = 42) | p-value | |
| Neutropenia (grade 3 or 4) | 43 (100) | 40 (95.2) | 0.241 |
| Neutropenia (grade 4) | 40 (93.0%) | 38 (90.5) | 0.713 |
| FN | 12 (27.9%) | 4 (9.5%) | 0.050 |
| Admission | 17 (39.5) | 9 (21.4%) | 0.099 |
| Hospitalization duration (days) | 2.0 ± 3.8 | 0.7 ± 1.5 | 0.041 |
| Outpatient costs (USD) | 227.0 ± 166.7 | 253.8 ± 58.7 | 0.325 |
| Inpatient costs (USD) | 137.7 ± 186.4 | 26.4 ± 60.1 | 0.001 |
| Total cost (USD) | 364.7 ± 271.6 | 279.6 ± 42.6 | 0.049 |
| Dose reduction or delay | 7 (16.3) | 3 (7.1) | 0.313 |
| Anemia | 3 (7.0) | 1 (2.4) | 0.616 |
| Thrombocytopenia | 8 (18.6) | 6 (14.3) | 0.771 |
| Liver function abnormality | 5 (11.6%) | 7 (16.7) | 0.549 |
| Renal failure | 1 (2.3) | 0 (0) | 1.000 |
| Transfusion | 4 (9.3) | 2 (4.8) | 0.676 |
| Infection | 5 (11.6) | 4 (9.5) | 1.000 |
| Death | 2 (4.7) | 0 | 0.494 |
Data are expressed as number (%)
| Variable | OR | 95% Confidence interval | p-value |
|---|---|---|---|
| Age (years) < 60 ≥ 60 | 1 1.700 | 0.540–5.347 | 0.364 |
| Menopause Premenopausal menopausal | 1 0.947 | 0.307–2.917 | 0.924 |
| BMI (kg/m2) < 25 ≥ 25 | 1 0.688 | 0.248–1.903 | 0.471 |
| IPC guidance Yes No | 1 3.677 | 1.078–12.543 | 0.038 |
| Comorbidities No Yes | 1 4.026 | 1.081–14.990 | 0.038 |
| Histologic type IDC ILC Others | 1 2.231 0.991 | 0.188–26.496 0.191–5.142 | 0.525 0.992 |
| T stage T1 T2 T3–T4 | 1 0.524 7.333 | 0.159–1.726 0.595–90.332 | 0.288 0.120 |
| N stage 0 1 2 3 | 1 2.545 2.154 1.400 | 0.503–12–891 0.336–13.804 0.103–19.012 | 0.259 0.418 0.800 |
| Estrogen receptor Negative Positive | 1 1.268 | 0.426–3.775 | 0.669 |
| Progesterone receptor Negative Positive | 1 0.610 | 0.195–1.905 | 0.395 |
| HER2 Negative Positive | 1 1.301 | 0.400–4.234 | 0.662 |
| BMI, body mass index; BSA, body surface area; DM, diabetes mellitus, HER2, human epidermal growth factor receptor 2; IPC, infection prevention and control | |||
| Variable | OR | 95% Confidence interval | p-value |
|---|---|---|---|
| IPC guidance Yes No | 1 4.668 | 1.238–17.602 | 0.023 |
| Comorbidities No Yes | 1 5.554 | 1.294–23.843 | 0.021 |
| IPC, infection prevention and control | |||
The three chemotherapy regimens most frequently used in breast cancer patients with axillary lymph node metastasis are AC-T (doxorubicin, cyclophosphamide, docetaxel), AT (doxorubicin, paclitaxel), and TAC. According to the National Comprehensive Cancer Network (NCCN) guidelines, all three regimens pose a high risk of neutropenia and its complications (> 20%).[3]
Our study focused on the TAC regimen, which was the most likely to show the prophylactic effect of IPC due to the high incidence of FN. Six-cycle TAC has the advantage of similar efficacy, but with a shorter treatment period, than eight-cycle AC followed by docetaxel.[13] However, the TAC regimen has a very high rate of FN, with CIN occurring in 100% of patients receiving TAC chemotherapy and FN in 42.5–63.4%.[8, 14] In our study, 97.6% patients developed CIN and 18.8% developed FN.
Chemotherapy-induced FN is a severe adverse effect that can delay the chemotherapy schedule, reduce the relative dose intensity, and increase the hospitalization period, which increases costs.[15, 16] In addition, FN can cause life-threatening infections, with fatality rates of 5–11%.[16] The mortality rate of FN in our study was 12.5% (2/14), and there was no death in the IPC group. Risk factors for FN include age, performance status, gender, comorbidities, laboratory abnormalities, BMI, chemotherapy regimen, neutropenia prophylaxis, tumor type, disease progression, and genetic risk factors.[17] In this study, these factors were controlled or analyzed, and only IPC and comorbidity were independently related to the development of FN.
The use of prophylactic G-CSF improves the prognosis of patients on the TAC regimen by lowering the incidence and duration of FN.[15] The NCCN, American Society of Clinical Oncology, and European Organization for the Research and Treatment of Cancer guidelines recommend routine use of primary G-CSF prophylaxis for high-risk cases (risk of FN > 20%) based on several randomized controlled trials.[18–20] The use of prophylactic ciprofloxacin can also lower the incidence of FN.[5] Despite these efforts, however, the rates of FN and its complications are still high.[5–8] In addition, the side effects of these prophylactic drugs cannot be ignored. Ciprofloxacin can cause pancytopenia and G-CSF is associated with the development of acute myeloid leukemia.[21, 22] In comparison, mask wearing and physical distancing are free from the potential risks of various pharmaceutical preventive methods.
All patients in this study had an ECOG score of 0, and received primary prophylactic pegfilgrastim to prevent FN and its complications, as well as prophylactic antibiotics when grade 4 NIC developed. The patients received all of these prophylactic drugs, and additional IPC significantly reduced the FN incidence rate, hospitalization duration, and hospital costs.
One of the main causes of fever in CIN patients is respiratory infection, which has a high mortality rate. Most respiratory infections in FN are bacterial or fungal, which can be controlled to some extent with drugs. However, viruses are also a cause, and one study detected a virus in 41% of patients.[9, 23] After the COVID-19 outbreak, the World Health Organization and Centers for Disease Control promoted mask wearing and physical distancing. This prevention guidance has proven effective against the transmission of respiratory diseases.[12, 24, 25] Our study showed that these guidelines were also effective in reducing the likelihood of FN in patients receiving TAC.
There were limitations to this study. First, it was retrospective. However, it was conducted under conditions controlled by the state due to the pandemic, it should have higher reliability than other retrospective studies. Second, the number of patients was insufficient for a single-center study. However, the TAC regimen has a high incidence of FN and the preventive effect of IPC was better than expected; significant results were obtained despite the small study population.
IPC reduces the occurrence of FN and reduces hospitalization duration and costs. It should be performed during chemotherapy in all patients at high risk of developing FN.
Contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Ye-Won Jeon], [Hongki Gwak] and [Young-Jin Suh]. The first draft of the manuscript was written by [HG] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Competing Interests
The authors have no relevant financial or non-financial interests to disclose.
Author Contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Ye-Won Jeon], [Hongki Gwak] and [Young-Jin Suh]. The first draft of the manuscript was written by [HG] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Ethics approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the institutional review board of the Catholic University of Korea (27-February-2022 / VC22RASI0019)
Consent to participate
Institutional Review Board waived the informed consent for this retrospective study.
Consent to publish
Institutional Review Board waived the informed consent for this retrospective study.