CLINICAL REVIEW Febrile neutropenia
CLINICAL REVIEW
ar Layar
Outpatient management of febrile neutropenia associated with cancer chemotherapy: Risk stratification and treatment review Nisha Pherwani, Joanna M. Ghayad, Lisa M. Holle, and Emilie L. Karpiuk
F
ebrile neutropenia (FN) is a common complication seen in patients with cancer who are receiving chemotherapy. It has been estimated that 10–50% of patients with solid tumors and more than 80% of patients with hematologic malignancies develop FN during at least one chemotherapy administration.1 Neutropenia is widely defined as an absolute neutrophil count (ANC) of less than 500 cells/mm3 and fever (defined as one measured temperature over 38.3 °C or a temperature consistently at or above 38.0 °C for more than one hour).2,3 Due to potentially serious sequelae, FN has traditionally been managed by hospitalization of patients and empirical treatment with i.v. broad-spectrum antibiotics. FN may lead to cancer treatment delays and antineoplastic dose modifications, thereby affecting survival and increasing mortality.4 Furthermore, serious complications of FN can occur, such as death from gram-negative bacteremia and sepsis, hypotension, altered mental status, and renal dysfunction.5 However, with the advent
Purpose. Strategies for the management of chemotherapy-induced febrile neutropenia (FN), including assessment tools for determining which patients are at low risk for FN complications and can be treated in the outpatient setting, are discussed. Summary. Due to the potential for lifethreatening complications, the development of FN in patients receiving cancer chemotherapy traditionally prompted hospitalization and i.v. antimicrobial therapy, but there is convincing published evidence that an identifiable subset of patients can be safely treated as outpatients. Two validated assessment tools recommended for identifying patients at low risk for FN complications are the Talcott classification system and the Multinational Association for Supportive Care in Cancer (MASCC) risk index; the MASCC index is superior in terms of sensitivity and negative predictive value but has lower
of effective antibiotics, these complications of FN are rare, and associated mortality rates are low. A review of 55,000 hospitalizations for adult FN in U.S. hospitals found a mean mortality risk of 2.8%.6
Nisha Pherwani, Pharm.D., BCOP, is Clinical Director, Oncology, Cardinal Health, Innovative Delivery Solutions, Houston, TX. Joanna M. Ghayad, Pharm.D., BCOP, is Medical Science Liaison, United Therapeutics Corporation, Research Triangle Park, NC. Lisa M. Holle, Pharm.D., BCOP, is Assistant Clinical Professor, Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs. Emilie L. Karpiuk, Pharm.D., BCPS, is Oncology Pharmacist, Froedtert Hospital, Milwaukee, WI.
specificity. In low-risk FN cases, outpatient oral antimicrobial therapy has been shown to be a safe and effective alternative to i.v. therapy for both inpatients and outpatients; current practice guidelines recommend an oral fluoroquinolone (e.g., ciprofloxacin) in combination with oral amoxicillin–clavulanate. The guidelines emphasize that in certain cases of FN (e.g., those involving prolonged or pronounced neutropenia or serious comorbidities), inpatient i.v. therapy is required. Conclusion. Pharmacists can play an important role in the management of chemotherapy-associated FN through involvement in risk assessment to identify candidates for outpatient oral antimicrobial therapy, selection of appropriate pharmacotherapy, drug therapy monitoring, and development of institutional guidelines or pathways. Am J Health-Syst Pharm. 2015; 72:619-31
While FN in patients with cancer can lead to life-threatening complications, a growing body of evidence shows that a subset of patients, such as those with solid tumors, are at a substantially lower risk and can be
Address correspondence to Dr. Pherwani (nisha.pherwani@ cardinalhealth.com). The authors have declared no potential conflicts of interest. Copyright © 2015, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/15/0402-0619. DOI 10.2146/ajhp140194
Am J Health-Syst Pharm—Vol 72 Apr 15, 2015
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CLINICAL REVIEW Febrile neutropenia
treated in the outpatient setting.7 By providing these lower-risk patients with treatment in the outpatient setting, patients have increased convenience, less exposure to hospitalacquired infections, and reduced healthcare costs.2 As management of the patient with cancer has primarily moved to the outpatient setting, it makes sense that providers prefer outpatient treatment options for FN in the low-risk patient. Various guidelines, including those from the American Society of Clinical Oncology (ASCO), Infectious Diseases Society of America (IDSA), and National Comprehensive Cancer Network (NCCN), have been developed to address the management of these low-risk patients.2,3,8 The twofold purpose of this article is to discuss the treatment of FN in outpatients and to identify differences between the guidelines. Risk stratification for FN More than 40 years ago, it was recognized that some characteristics of neutropenia predisposed patients to a febrile episode or were more likely to result in an undesirable outcome; these characteristics include a very low neutrophil count, a rapid decrease in neutrophil counts, a long duration of neutropenia (seven days or longer), hematologic malignancy, more intense chemotherapy, older age, and preexisting infections.3,9,10 It was also recognized that neutro-
penic patients are a heterogeneous population, in which some patients remain stable during antimicrobial therapy and therefore may not require hospitalization. Investigators have attempted to stratify the group of patients with FN who may be candidates for outpatient antimicrobial therapy. Two assessments have been validated in clinical trials to evaluate the risk of complications in a patient with FN: the Talcott classification system and the Multinational Association for Supportive Care in Cancer (MASCC) risk index. Talcott classification. The Talcott classification system classifies patients with FN into four groups (Table 1), with group 4 patients identified as candidates for outpatient therapy.11 The Talcott system was first published in 1988 using data from a single center. The investigators retrospectively reviewed 261 episodes of FN in 184 adult patients. They found that major risk factors could be assessed within 24 hours of presentation. Fever was defined as a temperature of ≥38 °C. Thirty-six variables were evaluated by stepwise logistic regression analysis. Most of the variables were not predictive of complications. Only three risk classifications were independently predictive of major complications, with complication rates of 34% in inpatients (group 1), 55% in outpatients with comorbidities (group 2), and 31% in patients with uncontrolled cancer (group 3); patients in
Table 1.
Talcott Classification System for Identifying Patients With LowRisk Febrile Neutropenia11 Group
Description
1
Patients hospitalized at onset of fever and neutropenia (inpatient at presentation) Outpatients at presentation but with comorbidities that required hospitalization Outpatients at presentation with uncontrolled cancer but with no comorbidities Outpatients at presentation with no comorbidities and controlled cancer
2 3 4
620
Am J Health-Syst Pharm—Vol 72 Apr 15, 2015
group 4 (i.e., outpatients without comorbidities or uncontrolled cancer) had only a 2% risk of developing life-threatening complications of FN. During a later comparison of available risk stratification systems, the Talcott classification system was found to have low sensitivity (30%) and was associated with a high misclassification rate (59%).7 Subsequently, investigators further evaluated the Talcott classification system in a prospective two-center validation study of 444 patients with FN (defined as an ANC of
CLINICAL REVIEW
ar Layar
Outpatient management of febrile neutropenia associated with cancer chemotherapy: Risk stratification and treatment review Nisha Pherwani, Joanna M. Ghayad, Lisa M. Holle, and Emilie L. Karpiuk
F
ebrile neutropenia (FN) is a common complication seen in patients with cancer who are receiving chemotherapy. It has been estimated that 10–50% of patients with solid tumors and more than 80% of patients with hematologic malignancies develop FN during at least one chemotherapy administration.1 Neutropenia is widely defined as an absolute neutrophil count (ANC) of less than 500 cells/mm3 and fever (defined as one measured temperature over 38.3 °C or a temperature consistently at or above 38.0 °C for more than one hour).2,3 Due to potentially serious sequelae, FN has traditionally been managed by hospitalization of patients and empirical treatment with i.v. broad-spectrum antibiotics. FN may lead to cancer treatment delays and antineoplastic dose modifications, thereby affecting survival and increasing mortality.4 Furthermore, serious complications of FN can occur, such as death from gram-negative bacteremia and sepsis, hypotension, altered mental status, and renal dysfunction.5 However, with the advent
Purpose. Strategies for the management of chemotherapy-induced febrile neutropenia (FN), including assessment tools for determining which patients are at low risk for FN complications and can be treated in the outpatient setting, are discussed. Summary. Due to the potential for lifethreatening complications, the development of FN in patients receiving cancer chemotherapy traditionally prompted hospitalization and i.v. antimicrobial therapy, but there is convincing published evidence that an identifiable subset of patients can be safely treated as outpatients. Two validated assessment tools recommended for identifying patients at low risk for FN complications are the Talcott classification system and the Multinational Association for Supportive Care in Cancer (MASCC) risk index; the MASCC index is superior in terms of sensitivity and negative predictive value but has lower
of effective antibiotics, these complications of FN are rare, and associated mortality rates are low. A review of 55,000 hospitalizations for adult FN in U.S. hospitals found a mean mortality risk of 2.8%.6
Nisha Pherwani, Pharm.D., BCOP, is Clinical Director, Oncology, Cardinal Health, Innovative Delivery Solutions, Houston, TX. Joanna M. Ghayad, Pharm.D., BCOP, is Medical Science Liaison, United Therapeutics Corporation, Research Triangle Park, NC. Lisa M. Holle, Pharm.D., BCOP, is Assistant Clinical Professor, Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs. Emilie L. Karpiuk, Pharm.D., BCPS, is Oncology Pharmacist, Froedtert Hospital, Milwaukee, WI.
specificity. In low-risk FN cases, outpatient oral antimicrobial therapy has been shown to be a safe and effective alternative to i.v. therapy for both inpatients and outpatients; current practice guidelines recommend an oral fluoroquinolone (e.g., ciprofloxacin) in combination with oral amoxicillin–clavulanate. The guidelines emphasize that in certain cases of FN (e.g., those involving prolonged or pronounced neutropenia or serious comorbidities), inpatient i.v. therapy is required. Conclusion. Pharmacists can play an important role in the management of chemotherapy-associated FN through involvement in risk assessment to identify candidates for outpatient oral antimicrobial therapy, selection of appropriate pharmacotherapy, drug therapy monitoring, and development of institutional guidelines or pathways. Am J Health-Syst Pharm. 2015; 72:619-31
While FN in patients with cancer can lead to life-threatening complications, a growing body of evidence shows that a subset of patients, such as those with solid tumors, are at a substantially lower risk and can be
Address correspondence to Dr. Pherwani (nisha.pherwani@ cardinalhealth.com). The authors have declared no potential conflicts of interest. Copyright © 2015, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/15/0402-0619. DOI 10.2146/ajhp140194
Am J Health-Syst Pharm—Vol 72 Apr 15, 2015
619
CLINICAL REVIEW Febrile neutropenia
treated in the outpatient setting.7 By providing these lower-risk patients with treatment in the outpatient setting, patients have increased convenience, less exposure to hospitalacquired infections, and reduced healthcare costs.2 As management of the patient with cancer has primarily moved to the outpatient setting, it makes sense that providers prefer outpatient treatment options for FN in the low-risk patient. Various guidelines, including those from the American Society of Clinical Oncology (ASCO), Infectious Diseases Society of America (IDSA), and National Comprehensive Cancer Network (NCCN), have been developed to address the management of these low-risk patients.2,3,8 The twofold purpose of this article is to discuss the treatment of FN in outpatients and to identify differences between the guidelines. Risk stratification for FN More than 40 years ago, it was recognized that some characteristics of neutropenia predisposed patients to a febrile episode or were more likely to result in an undesirable outcome; these characteristics include a very low neutrophil count, a rapid decrease in neutrophil counts, a long duration of neutropenia (seven days or longer), hematologic malignancy, more intense chemotherapy, older age, and preexisting infections.3,9,10 It was also recognized that neutro-
penic patients are a heterogeneous population, in which some patients remain stable during antimicrobial therapy and therefore may not require hospitalization. Investigators have attempted to stratify the group of patients with FN who may be candidates for outpatient antimicrobial therapy. Two assessments have been validated in clinical trials to evaluate the risk of complications in a patient with FN: the Talcott classification system and the Multinational Association for Supportive Care in Cancer (MASCC) risk index. Talcott classification. The Talcott classification system classifies patients with FN into four groups (Table 1), with group 4 patients identified as candidates for outpatient therapy.11 The Talcott system was first published in 1988 using data from a single center. The investigators retrospectively reviewed 261 episodes of FN in 184 adult patients. They found that major risk factors could be assessed within 24 hours of presentation. Fever was defined as a temperature of ≥38 °C. Thirty-six variables were evaluated by stepwise logistic regression analysis. Most of the variables were not predictive of complications. Only three risk classifications were independently predictive of major complications, with complication rates of 34% in inpatients (group 1), 55% in outpatients with comorbidities (group 2), and 31% in patients with uncontrolled cancer (group 3); patients in
Table 1.
Talcott Classification System for Identifying Patients With LowRisk Febrile Neutropenia11 Group
Description
1
Patients hospitalized at onset of fever and neutropenia (inpatient at presentation) Outpatients at presentation but with comorbidities that required hospitalization Outpatients at presentation with uncontrolled cancer but with no comorbidities Outpatients at presentation with no comorbidities and controlled cancer
2 3 4
620
Am J Health-Syst Pharm—Vol 72 Apr 15, 2015
group 4 (i.e., outpatients without comorbidities or uncontrolled cancer) had only a 2% risk of developing life-threatening complications of FN. During a later comparison of available risk stratification systems, the Talcott classification system was found to have low sensitivity (30%) and was associated with a high misclassification rate (59%).7 Subsequently, investigators further evaluated the Talcott classification system in a prospective two-center validation study of 444 patients with FN (defined as an ANC of
