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Indian Journal of Medical and Paediatric Oncology
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ORIGINAL ARTICLE
Year : 2019  |  Volume : 40  |  Issue : 2  |  Page : 249-256  

Assessment of chemotherapy-induced febrile neutropenia in cancer patients


1 Department of Pharmacy Practice, NGSM Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangalore, Karnataka, India
2 Department of Medical Oncology, K. S. Hegde Medical Academy, Justice K. S. Hegde Charitable Hospital, Mangalore, Karnataka, India

Date of Web Publication17-Oct-2019

Correspondence Address:
Vijith Shetty
Department of Medical Oncology, K. S. Hegde Medical Academy, Justice K. S. Hegde Charitable Hospital, Deralakatte, Mangalore - 575 018, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmpo.ijmpo_31_18

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  Abstract 

Purpose: Chemotherapy-induced febrile neutropenia (CIFN) is an adverse drug reaction which needs medical attention. The treatment options for the CIFN are mandatory to improve treatment outcomes and quality of life. Methods: A prospective observational study was conducted in the in-patients and out-patients of oncology department who received chemotherapy from October 2016 to March 2017. The information such as demographics (age, gender, and comorbidities), complaints on admission, hematological investigations (neutrophil counts, platelet counts, hemoglobin levels, erythrocyte sedimentation rate, and white blood cells), type of tumor, stage of cancer, prophylaxis, cycle of antineoplastic chemotherapy that cause febrile neutropenia, treatment history, and outcome data were obtained from the patient's clinical record. The Multinational Association for Supportive Care in Cancer score and Absolute Neutrophil Count grading was used to predict the patient's risk of developing CIFN. Results: Out of 200 patients, 19 patients developed 22 episodes of CIFN. The overall occurrence of CIFN during the study was 9.5%. The higher incidence of CIFN has been observed among male gender (57.89%), stage III patients (42.10%), solid tumor (73.68%), and double chemotherapy regimen (59.1%). The higher incidence of CIFN was developed in I cycle (36.36%) followed by II cycle (22.72%) and VI cycle (18.18%). Conclusions: The incidence of CIFN during the study was 9.5%. In the 19 chemotherapy-induced FN patients, there has no significant effect of prophylaxis to prevent the febrile neutropenia.

Keywords: Adverse drug reactions, cancer, chemotherapy, febrile neutropenia, incidence


How to cite this article:
Philip ML, Saj N, Sebastian AM, Mateti UV, Shetty V. Assessment of chemotherapy-induced febrile neutropenia in cancer patients. Indian J Med Paediatr Oncol 2019;40:249-56

How to cite this URL:
Philip ML, Saj N, Sebastian AM, Mateti UV, Shetty V. Assessment of chemotherapy-induced febrile neutropenia in cancer patients. Indian J Med Paediatr Oncol [serial online] 2019 [cited 2019 Nov 13];40:249-56. Available from: http://www.ijmpo.org/text.asp?2019/40/2/249/269464




  Introduction Top


Cancer is the second most common cause of morbidity and mortality in most countries. Chemotherapy is an important treatment option in most cancers. Chemotherapy regimens are associated with variable period of myelosuppression.[1] Chemotherapy suppresses the bone marrow. Thus, neutrophils, white blood cells (WBC), platelets, and red blood cells which are produced by the bone marrow decrease in count making the person more vulnerable to infections. Decrease in the count of neutrophils with fever can lead to a febrile neutropenic condition.[2] Febrile neutropenia (FN) is defined as a “single oral temperature of ≥38.5°C or sustained temperature of ≥38.0°C over a 1 h period with <500 neutrophils/mm or <1000 neutrophils/mm with a predicted decline to 500 cells/mm over 2 days”. The incidence and severity are based on the neutrophil count.[3]

A survey of literature states that the incidence of chemotherapy-induced FN (CIFN) was reported in: paclitaxel and carboplatin (1%), docetaxel and carboplatin (2%), doxorubicin (3%), paclitaxel (6%), irinotecan and nedaplatin (7%), adriamycin and cisplatin (11%), docetaxel and gemcitabine (33%), irinotecan and mitomycin C (40%), etc.[4] The Higher risk of CIFN was observed in patients treated with prophylaxis chemotherapy regimen. The risk of CIFN can be obtained from the Multinational Association of Supportive Care in Cancer (MASCC) score and from absolute neutrophil count (ANC). MASCC score of >21 indicates low risk and <21 indicates high risk of FN.[5] FN is divided into Grades 1-4 based on the ANC counts (cells/mm 3).[6]

The duration of hospitalization is a predictive factor in evaluating the severity of CIFN. High-dose chemotherapeutic regimen, hematological malignancies, comorbidities, infections and can upsurge the duration of FN and consequently lead hospitalization.[7] Based on the risk of FN, prophylactic treatment such as granulocyte monocyte colony-stimulating factors (CSF) or granulocyte CSF (G-CSF) is endorsed as a standard in the chemotherapy regimen. Antibiotics are also considered as prophylactic agents due to increased vulnerability to infection and as a treatment option for CIFN.[8] Treatment options for the management of CIFN depend on age, gender, comorbidities, primary or secondary prophylaxis, the severity of the neutropenia, appropriate prophylactic use, antibiotics used and the response of the patient to the therapy.[5]


  Methods Top


Study design

A prospective observational study was conducted for a period of 6 months (October 2016–March 2017). This study was conducted in patients admitted to and visiting the outpatient setting in the Oncology Department of Justice K. S. Hegde Charitable Hospital, Dakshina Kannada, Deralakatte, Mangaluru.

Ethical approval

The study was approved by the Institutional Ethics Committee (REF: INST. EC/EC/97/2016–2017) at K. S. Hegde Medical Academy, Mangalore.

Study criteria

The inclusion criteria consisted of patients of all age groups of either gender, all cancerous patients receiving chemotherapy and who have given the written informed consent form. Acquired or congenital neutropenic patients, radiation-induced neutropenia and patients not willing to participate in the study were excluded from the study.

Data collection

Information such as demographics (age, gender, and comorbidities), complaints on admission, hematological investigations (neutrophil counts, platelet counts, hemoglobin levels, erythrocyte sedimentation rate [ESR], WBC), type of tumor, cycles and antineoplastic chemotherapy that cause FN, treatment history, option and outcome data were obtained from the patients' clinical records. Details necessary for evaluation regarding concomitant medications, comorbidities, tumor type, stage of cancer, prophylaxis, and dose modification for causality assessment and management that helps to assess the incidence of CIFN and their expected outcomes.

All the prescriptions of the study population were screened for CIFN. The details regarding temperature, length of hospitalization, and laboratory reports were obtained from the patient's clinical record. Demographics of the patients were studied to find out the pattern of adverse drug reactions (ADRs).

Identification of chemotherapy-induced febrile neutropenia

All the patients receiving chemotherapy were classified according to MASCC 2013 as patients at risk for serious complications of FN into high and low risk patients and CIFN was graded according to ANC.[6],[9] Patients who met the inclusion criteria were assessed for the incidence, causality assessment, severity assessment, preventable measures, evaluation of risk factors, and treatment outcome of CIFN.

Identification of CIFN was done based on regular follow-up of the patients by analyzing the subjective findings. Consultant oncologist assessed suspected ADRs and relevant data were filled in the case record form. The details of laboratory manifestations, medications used were recorded in the case record form and ADR form.

Data of the reported ADRs were evaluated to understand the pattern of the ADRs with respect to patient demographics, the severity of the reaction, characteristics of the drug involved, the outcome of the reaction and the management of FN.

Analysis of chemotherapy-induced febrile neutropenia

To assess the likelihood that a drug has caused the reaction, causality assessment was done using Naranjo scale (1991) which classifies CIFN as certain, probable, possible and unlikely and the WHO probability scale as certain probable, possible, unlikely, unclassified and conditional to be drug-induced depending on the level of association.[10],[11] Depending on the severity, CIFN was classified into mild, moderate, and severe reactions using the criteria developed by Hartwig et al. and ANC for severity assessment.[9],[12] CIFN was categorized into definitely preventable, probably preventable and not preventable using the criteria of Schumock and Thornton modified.[13]

Predisposing factors

Factors that could have predisposed to the occurrence of CIFN in the individual reports were evaluated. Predisposing factors were generally classified for the study into age, gender, multiple disease state, and polypharmacy.

Management of chemotherapy induced febrile neutropenia

Management of CIFN was categorized as drug withdrawal, dose reduction, additional treatment for further complications, and no change in regimen with any additional treatment. Spontaneous reporting of suspected ADRs by the physician, pharmacist, and nurse can facilitate prevention of CIFN.

Statistical analysis

Frequency and percentage were used to summarize the categorical variables. Descriptive statistics such as mean, standard deviation, and median were calculated for continuous variables. Chi-square test or Fisher's exact test was applied to test the association between categorical variables. Correlation between the continuous variables were tested by using Spearman's correlation and tested for its significance by using independent sample t-test with value P < 0.05 considered as statistically significant. Statistical software was used to analyze the data. The statistical analysis was performed by using SPSS version 16 (IBM Corp., Armonk, NY, United States of America).


  Results Top


During the study, a total of 200 patients with different types of cancers receiving chemotherapy regimen were recruited. Out of 200 patients, 19 patients developed 22 episodes of CIFN. The overall occurrence of CIFN during the study was 9.5%. In the study, age group of 45–60 years (52.63%) exhibited a higher incidence of CIFN compared to other age groups. The mean age of the patients with and without CIFN was 55.26 ± 9.42 and 53.61 ± 12.69 years, respectively, (P = 0.689). Occurrence of CIFN was predominantly higher in males (57.89%) than in females (42.10%). CIFN patients exhibited significantly less social habits such as smoking, alcohol use, and substance abuse. Most of the patients who developed CIFN had diabetes mellitus (15.78%), followed by hypertension (10.52%) and other comorbidities.

Cancer is subdivided into solid and hematological tumors. Solid tumors (73.68%) were prominent than hematological (26.31%) in patients who developed CIFN. Most of the patients in this study were diagnosed with stage III of cancer (44%), and among the 19 CIFN cases, patients diagnosed at stage III showed a higher incidence of CIFN (42.10%) than the other stages. Out of 200 patients, 9.5% of the patients developed a fever along with neutropenia. All these 9.5% of the patients were CIFN (n = 19). The median length of hospital stay for CIFN patients (n = 19) was 6 days and the interquartile (Q3–Q1) ranged from 15 to 10 days. Prophylaxis is commonly administered along with chemotherapy regimens to prevent CIFN. Out of 200 patients, 155 received G-CSF as prophylaxis and 45 were not. Levofloxacin was the only antibiotic given as prophylaxis in 3 patients who were at high risk. Among the 19 CIFN cases reported, 17 patients showed the incidence of CIFN even though they received G-CSF as prophylaxis. The details regarding the characteristics of CIFN are summarized in [Table 1]. Among the 19 CIFN patients, 10.52% were in low risk and 89.47% were in high-risk category based on MASCC. In the ANC analysis, higher incidence of CIFN was exhibited in Grade 1: Cycle 4 (78.94%), Grade 2: Cycle 1 and 2 (10.52%), Grade 3: Cycle 3 (15.78%), and Grade 4: Cycle 6 (42.10%). The details regarding the predictors of risk assessment are depicted in [Table 2]. Out of 200 patients, majority of the patients received double regimen chemotherapy. Out of 22 episodes of CIFN, double regimen patients developed higher incidence of CIFN (59.1%). Out of 19 patients, the first (36.36%) and second (22.72%) cycles of chemotherapy exhibited higher incidence of CIFN cases compared to other chemotherapy cycles. The details regarding the chemotherapy regimens and cycle are summarized in [Table 3].
Table 1: Characteristics of patients with and without chemotherapy induced febrile neutropenia

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Table 2: Predictors for risk assessment in patients with and without chemotherapy induced febrile neutropenia

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Table 3: Chemotherapy regimen and cycle in chemotherapy induced febrile neutropenia patients

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Causality, severity, preventability, and predictability of chemotherapy-induced febrile neutropenia

The WHO probability scale was used to analyze the suspected CIFN and the scale showed that 81.81% of CIFN reactions were probably followed by certain (13.63%) and possible (4.54%). To assess the causality of the suspected CIFN, Naranjo's causality assessment scale was used. The scales showed that 77.27% of CIFN were probable followed by 13.63% were certain and 9.09% were possible. Severity assessment scale was used to classify the intensity of CIFN cases. Mortality rate due to CIFN among the 19 patients were 2 (%). Majority of the CIFN cases had moderate (level 4a) scale of severity (36.36%). Preventability assessment for CIFN was done using Schumock and Thornton scale. The scale showed that 27.27% of CIFN were not preventable and 72.72% were probably preventable. All the 22 episodes of CIFN reported were predictable. Among 19 CIFN patients, 40.90% of drugs were withdrawn, 4.5% of doses were altered, and 54.54% had no change. Majority of the CIFN cases were treated specifically (86.36%) and few were treated symptomatically (13.63%), Outcome of the patients depends on the intensity of the reaction. Majority of the CIFN patients were recovered 59.09% and the others ceasing the drug that has caused the reaction can confirm the causative agent. In this study, out of 22 CIFN reactions, 12 (54.53%) were dechallenged. Reintroducing the drug can identify the causative drug that has caused CIFN. Out of 22 CIFN reactions, 6 (27.26%) were rechallenged. The details regarding the assessment of CIFN are depicted in [Table 4]. Majority of the patients had breast cancer (18.5%), but FN was mostly observed in patients diagnosed with stomach cancer (15.7%). Out of the 19 CIFN patients, 16 experienced FN once whereas 3 of them experienced FN twice. The regimen that caused FN twice were Carboplatin-Etoposide, Carboplatin-Placlitaxel and Adriamycin + Bleomycin + Vincristine + Dacarbazine regimen. The detailed description of cancer with chemotherapy regimen in patients with and without FN is depicted in [Table 5].
Table 4: Causality, severity, preventability and predictability of chemotherapy induced febrile neutropenia

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Table 5: Types of cancer and chemotherapy regimen administered in patients with and without chemotherapy induced febrile neutropenia

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  Discussion Top


The development of myelosuppression during chemotherapy is influenced by the demographics of the patients (age, gender, and comorbidities), cancer types, stages, and characteristics of the chemotherapy regimen used.

Higher incidence of CIFN was exhibited in the age group between 45 and 60 years (52.63%) among 19 CIFN patients compared to other groups. In a study conducted by Catic et al., higher incidence of CIFN was observed in the age group of 41–60 years (48%) among 27 CIFN patients.[14] The present study is in concurrence with the Catic et al., study, where the results showed a higher incidence of CIFN in the age group of 40–60 years.[14]

Out of 19 CIFN patients, 57.89% of patients were male and 42.10% were female. A study conducted by Sammut and Mazhar et al., analyzed 32 CIFN cases in which 62.5% were female and 37.5% were male.[15] The present study was contradictory to the reference study. In the present study, solid tumors exhibited higher incidence of CIFN (73.68%) than hematological tumors (26.31%). In a study conducted by Ahn et al., out of 396 episodes of CIFN, solid tumors (71.5%) were predominantly more than hematological (28.5%).[9] Hence, this study is in agreement with the previous study were solid tumors shows higher CIFN events.

Out of 200 patients, majority of the patients received double regimen chemotherapy (59.1%) and showed higher incidence of CIFN. In a study conducted by Hashiguchi et al., among 291 patients, the most common chemotherapy was paclitaxel and carboplatin (double regimen) which exhibited 50.5% of CIFN cases.[4] Hence, the present study resembles the previous study that double regimen shows higher incidence of CIFN. The median length of stay for patients who developed CIFN was 6 days. The P value was 0.00, which showed strong association between length of hospitalization and the development of CIFN. The study conducted by Weycker et al., reported that the median length of stay was 8.14 days for patients with CIFN.[16] The incidence of CIFN in each cycles varied, 36.63% were encountered in cycle 1 followed by 22.72% and 18.18% in cycle 2 and cycle 6, respectively. Culakova et al., reported 9.7% of CIFN in cycle 1 followed by 5.7% and 3.8% in cycle 2 and 3, respectively.[17] The present study is in correspondence with the previous study that incidence is more in cycle 1 and 2, but varied in the following cycles.

The MASCC risk index score was used to predict the risk of CIFN among the patients (n = 200), 50.5% of them were in low risk and 49.5% of them were in high-risk category of patients. Of the high-risk patients, 89.47% developed CIFN and 10.52% developed CIFN in low-risk patients. The P value for MASCC score was 0.001, which showed strong association with the risk of developing CIFN. A study conducted by Ahn et al., showed 90% of low-risk patients and 72% of high risk patients using MASCC risk index score, where 18.9% of high risk died.[9] Hence, this study is in correspondence with the previous study that MASCC score is used to predict low and high-risk patients. The incidence of CIFN in the study was 9.5%, similarly Shiota et al., conducted a study on 37 patients and the incidence of CIFN was 10.8%.[18]

The higher incidence of CIFN was shown in Stage 3 of cancer (42.10%), similarly Talwar et al., conducted a study, where most of the patients with CIFN presented in stage 3 (33.2%) and in Stage 4 (41.6%) of cancer.[19] To the best of our knowledge, this is the premier study to analyze the CIFN reactions by using causality, severity, preventability, and predictability scales. As per the WHO and Naranjo's scales, most of the CIFN reactions were classified as probably 81.82% and 77.2%, respectively. Out of 22 CIFN cases, 9.09% of mortality has been reported, and all the CIFN reactions were predictable. Preventability assessment scale showed that 27.27% of reactions are not preventable and 72.72% reactions are probably preventable. As management of CIFN among 19 patients, 40.90% of drugs were withdrawn, 4.5% of doses were altered, and 54.54% had no change. In addition, 86.36% were treated specifically whereas, 13.63% were treated symptomatically. Moreover, 50.09% of patients recovered, whereas 22.72% of patients continued in the same condition and 18.18% were fatal. The percentage of patients underwent dechallenge were 54.53% and rechallenge were 27.26%.


  Conclusions Top


In this study, the incidence of CIFN was 9.5%. The age group of 45–60 years (52.63%) showed higher incidence of CIFN compared to another age group. In gender-wise distribution, the occurrence of CIFN was predominantly higher in males (57.89%) than in females (42.10%). The patients diagnosed at stage 3 showed greater incidence of CIFN (42.10%) than the other stages. The solid tumors (73.68%) were prominent than hematological tumor (26.31%). The length of hospitalization had prolonged for all patients who developed CIFN with a median of 6 days. The patients who received double chemotherapy regimen (59.1%) showed a higher incidence of CIFN than the other chemotherapy regimens. The incidence of CIFN was higher in I and II cycles of chemotherapy showed 36.36% and 22.72%, respectively.

Acknowledgments

We are thankful to the authorities of Nitte (Deemed to be University), Mangaluru, India; Dr. Jayarama Shetty, Professor, Department of Oncology, Justice K. S. Hegde Charitable Hospital, Mangaluru; Dr. C. S. Shasty, Principal, NGSM Institute of Pharmaceutical Sciences, Mangaluru.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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