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.

Introduction

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 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_31_18#JR_3" xss=removed>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 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_31_18#JR_5" xss=removed>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

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>

Results

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].

1.  Rang HP, Ritter JM, Flower RJ, Henderson G. Drugs used for the treatment of infection and cancer. Rang and Dale's Pharmacology. Anticancer Drugs. 8th ed. London: Elsevier Churchill Livingstone; 2012: 676-90
2.  Morin PJ, Trent JM, Collins FS, Vogenstein B. Cancer Genetics. In: Kasper DC, Hauser SL, Jameson JL, Fauci AS, Longo DL, Loscalzo J. editors Harrison's Principles of Internal Medicine. Part 10. 19th ed. 3. Sec. 3. Ch. 101e United States of America: McGraw-Hill Education; 2016: 1-10
3.  Rosa RG, Goldani LZ. Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia. Antimicrob Agents Chemother 2014; 58: 3799-803
4.  Hashiguchi Y, Kasai M, Fukuda T, Ichimura T, Yasui T, Sumi T. et al. Chemotherapy-induced neutropenia and febrile neutropenia in patients with gynecologic malignancy. Anticancer Drugs 2015; 26: 1054-60
5.  Garnica M, Nouér SA, Pellegrino FL, Moreira BM, Maiolino A, Nucci M. et al. Ciprofloxacin prophylaxis in high risk neutropenic patients: Effects on outcomes, antimicrobial therapy and resistance. BMC Infect Dis 2013; 13: 356
6.  Yu MG, Villalobos RE, Juan-Bartolome MJ, Berba RP. Predictors of outcome and severity in adult Filipino patients with febrile neutropenia. Adv Hematol 2015; 2015: 920838
7.  Bengre ML, Venkatraya PM, Arun S, Prasad K, Gopalkrishna BK. Evaluation of the multinational association for supportive care in cancer (MASCC) score for identifying low risk febrile neutropaenic patients at a South Indian tertiary care centre. J Clin Diagnostic Res 2012; 6: 839-43
8.  Aapro M, Ludwig H, Bokemeyer C, Gascón P, Boccadoro M, Denhaerynck K. et al. Predictive modeling of the outcomes of chemotherapy-induced (febrile) neutropenia prophylaxis with biosimilar filgrastim (MONITOR-GCSF study). Ann Oncol 2016; 27: 2039-45
9.  Ahn S, Lee YS, Chun YH, Kwon IH, Kim W, Lim KS. et al. Predictive factors of poor prognosis in cancer patients with chemotherapy-induced febrile neutropenia. Support Care Cancer 2011; 19: 1151-8
10.  Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA. et al. Amethod for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239-45
11.  Mateti UV, Nekkanti H, Vilakkathala R, Rajakannan T, Mallayasamy S, Ramachandran P. et al. Pattern of angiotensin-converting enzyme inhibitors induced adverse drug reactions in South Indian teaching hospital. N Am J Med Sci 2012; 4: 185-9
12.  Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992; 49: 2229-32
13.  Gholami K, Shalviri G. Factors associated with preventability, predictability, and severity of adverse drug reactions. Ann Pharmacother 1999; 33: 236-40
14.  Catic T, Mekic-Abazovic A, Sulejmanovic S. Cost of febrile neutropenia treatment in bosnia and herzegovina. Mater Sociomed 2016; 28: 112-5
15.  Sammut SJ, Mazhar D. Management of febrile neutropenia in an acute oncology service. QJM 2012; 105: 327-36
16.  Weycker D, Li X, Edelsberg J, Barron R, Kartashov A, Xu H. et al. Risk and consequences of chemotherapy-induced febrile neutropenia in patients with metastatic solid tumors. J Oncol Pract 2015; 11: 47-54
17.  Culakova E, Poniewierski MS, Wolff DA, Dale DC, Crawford J, Lyman GH. et al. The impact of chemotherapy dose intensity and supportive care on the risk of febrile neutropenia in patients with early stage breast cancer: A prospective cohort study. Springerplus 2015; 4: 396
18.  Shiota M, Yokomizo A, Takeuchi A, Kiyoshima K, Inokuchi J, Tatsugami K. et al. Risk factors for febrile neutropenia in patients receiving docetaxel chemotherapy for castration-resistant prostate cancer. Support Care Cancer 2014; 22: 3219-26
19.  Talwar V, Nirni SS, Mallavarapu KM, Ramkumar A, Sinha N. Safety and tolerability of peg-grafeel™, a pegfilgrastim, for the prophylactic treatment of chemotherapy-induced neutropenia and febrile neutropenia: A prospective, observational, postmarketing surveillance study in India. South Asian J Cancer 2017; 6: 20-4

1.  Rang HP, Ritter JM, Flower RJ, Henderson G. Drugs used for the treatment of infection and cancer. Rang and Dale's Pharmacology. Anticancer Drugs. 8th ed. London: Elsevier Churchill Livingstone; 2012: 676-90
2.  Morin PJ, Trent JM, Collins FS, Vogenstein B. Cancer Genetics. In: Kasper DC, Hauser SL, Jameson JL, Fauci AS, Longo DL, Loscalzo J. editors Harrison's Principles of Internal Medicine. Part 10. 19th ed. 3. Sec. 3. Ch. 101e United States of America: McGraw-Hill Education; 2016: 1-10
3.  Rosa RG, Goldani LZ. Cohort study of the impact of time to antibiotic administration on mortality in patients with febrile neutropenia. Antimicrob Agents Chemother 2014; 58: 3799-803
4.  Hashiguchi Y, Kasai M, Fukuda T, Ichimura T, Yasui T, Sumi T. et al. Chemotherapy-induced neutropenia and febrile neutropenia in patients with gynecologic malignancy. Anticancer Drugs 2015; 26: 1054-60
5.  Garnica M, Nouér SA, Pellegrino FL, Moreira BM, Maiolino A, Nucci M. et al. Ciprofloxacin prophylaxis in high risk neutropenic patients: Effects on outcomes, antimicrobial therapy and resistance. BMC Infect Dis 2013; 13: 356
6.  Yu MG, Villalobos RE, Juan-Bartolome MJ, Berba RP. Predictors of outcome and severity in adult Filipino patients with febrile neutropenia. Adv Hematol 2015; 2015: 920838
7.  Bengre ML, Venkatraya PM, Arun S, Prasad K, Gopalkrishna BK. Evaluation of the multinational association for supportive care in cancer (MASCC) score for identifying low risk febrile neutropaenic patients at a South Indian tertiary care centre. J Clin Diagnostic Res 2012; 6: 839-43
8.  Aapro M, Ludwig H, Bokemeyer C, Gascón P, Boccadoro M, Denhaerynck K. et al. Predictive modeling of the outcomes of chemotherapy-induced (febrile) neutropenia prophylaxis with biosimilar filgrastim (MONITOR-GCSF study). Ann Oncol 2016; 27: 2039-45
9.  Ahn S, Lee YS, Chun YH, Kwon IH, Kim W, Lim KS. et al. Predictive factors of poor prognosis in cancer patients with chemotherapy-induced febrile neutropenia. Support Care Cancer 2011; 19: 1151-8
10.  Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA. et al. Amethod for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239-45
11.  Mateti UV, Nekkanti H, Vilakkathala R, Rajakannan T, Mallayasamy S, Ramachandran P. et al. Pattern of angiotensin-converting enzyme inhibitors induced adverse drug reactions in South Indian teaching hospital. N Am J Med Sci 2012; 4: 185-9
12.  Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992; 49: 2229-32
13.  Gholami K, Shalviri G. Factors associated with preventability, predictability, and severity of adverse drug reactions. Ann Pharmacother 1999; 33: 236-40
14.  Catic T, Mekic-Abazovic A, Sulejmanovic S. Cost of febrile neutropenia treatment in bosnia and herzegovina. Mater Sociomed 2016; 28: 112-5
15.  Sammut SJ, Mazhar D. Management of febrile neutropenia in an acute oncology service. QJM 2012; 105: 327-36
16.  Weycker D, Li X, Edelsberg J, Barron R, Kartashov A, Xu H. et al. Risk and consequences of chemotherapy-induced febrile neutropenia in patients with metastatic solid tumors. J Oncol Pract 2015; 11: 47-54
17.  Culakova E, Poniewierski MS, Wolff DA, Dale DC, Crawford J, Lyman GH. et al. The impact of chemotherapy dose intensity and supportive care on the risk of febrile neutropenia in patients with early stage breast cancer: A prospective cohort study. Springerplus 2015; 4: 396
18.  Shiota M, Yokomizo A, Takeuchi A, Kiyoshima K, Inokuchi J, Tatsugami K. et al. Risk factors for febrile neutropenia in patients receiving docetaxel chemotherapy for castration-resistant prostate cancer. Support Care Cancer 2014; 22: 3219-26
19.  Talwar V, Nirni SS, Mallavarapu KM, Ramkumar A, Sinha N. Safety and tolerability of peg-grafeel™, a pegfilgrastim, for the prophylactic treatment of chemotherapy-induced neutropenia and febrile neutropenia: A prospective, observational, postmarketing surveillance study in India. South Asian J Cancer 2017; 6: 20-4