ORIGINAL STUDIES

A Randomized, Double-Blind, Multicenter Study of Caspofungin Versus Liposomal Amphotericin B for Empiric Antifungal Therapy in Pediatric Patients With Persistent Fever and Neutropenia
Johan A. Maertens, MD,* Luis Madero, MD, Anne F. Reilly, MD, Thomas Lehrnbecher, MD, Andreas H. Groll, MD, Hasan S. Jafri, MD, Michael Green, MD,** Joseph J. Nania, MD, Michael R. Bourque, MS, Beth Ann Wise, MSEd, Kim M. Strohmaier, BS, Arlene F. Taylor, MS, Nicholas A. Kartsonis, MD, Joseph W. Chow, MD, Carola A. S. Arndt, MD, Ben E. dePauw, MD,*** and Thomas J. Walsh, MD, for the Caspofungin Pediatric Study Group
patients. Overall success rates 95% CI were 46.4% 33.4 59.5 for caspofungin and 32.0% 13.750.3 for L-AmB. Conclusions: Caspofungin and L-AmB were comparable in tolerability, safety, and efcacy as empiric antifungal therapy for persistently febrile neutropenic pediatric patients. Key Words: caspofungin, liposomal amphotericin B, empiric antifungal therapy, pediatric patients, fever and neutropenia (Pediatr Infect Dis J 2010;29: 415 420)

Background: Persistently febrile neutropenic children at risk for invasive fungal infections receive empiric antifungal therapy as a standard of care. However, little is known about the role of echinocandins and liposomal amphotericin B (L-AmB) for empiric antifungal therapy in pediatric patients. Methods: Patients between the ages of 2 to 17 years with persistent fever and neutropenia were randomly assigned to receive caspofungin (70 mg/m2 loading dose on day 1, then 50 mg/m2 daily maximum 70 mg/d ) or L-AmB (3 mg/kg daily) in a 2:1 ratio. Evaluation of safety was the primary objective of the study. Efcacy was also evaluated, with a successful outcome dened as fullling all components of a prespecied 5-part composite endpoint. Suspected invasive fungal infections were evaluated by an independent, treatment-blinded adjudication committee. Results: Eighty-two patients received study therapy (caspofungin 56, L-AmB 26), and 81 were evaluated for efcacy (caspofungin 56; L-AmB 25). Outcomes for safety and efcacy endpoints were similar for both study arms. Adverse drug-related event rates 95% condence interval were similar between the caspofungin and L-AmB groups (clinical 48.2% 34.7 62.0 versus 46.2% 26.6 66.6 ; laboratory 10.7% 4.0 21.9 versus 19.2% 6.6 39.4 ). Serious drug-related adverse events occurred in 1 (1.8%) of caspofungin-treated patients and 3 (11.5%) of L-AmB-treated
Accepted for publication December 9, 2009. From the *Acute Leukemia and Stem Cell Transplantation Unit, Department of Hematology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, Belgium; Pediatrics Hematology-Oncology, Hospital Universitario Nino Jesus, Madrid, Spain; Division of Oncology, Childrens Hospital of Philadelphia, Philadelphia, PA; Pediatric Hematology and Oncology, University of Frankfurt, Frankfurt, Germany; Infectious Disease Research Program, Department of Pediatric Hematology/Oncology, University Childrens Hospital of Munster, Munster, Germany; Division of Pediatric Infectious Diseases, De partment of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX; **Division of Infectious Diseases, Departments of Pediatrics, Surgery & Clinical and Translational Science, Childrens Hospital of Pittsburgh, Pittsburgh, PA; Vanderbilt University, Nashville, TN; Clinical ResearchInfectious Diseases, Merck Research Laboratories, North Wales, PA; Medical Communications, Merck Research Laboratories, North Wales, PA; Biostatistics & Research Decision Sciences, Merck Research Laboratories, North Wales, PA; Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; ***Blood Transfusion and Transplant Immunology, Radboud University, Nijmegen Medical Centre, Nijmegen, Netherlands; Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD. Hasan S. Jafri is currently at Infectious Disease, Clinical Research and Development, MedImmune, Gaithersburg, MD. Address for correspondence: Dr Thomas J. Walsh, MD, Pediatric Oncology Branch, National Cancer Institute, CRC 1-5750, 10 Center Drive, Bethesda, MD 20892. E-mail: walsht@mail.nih.gov. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journals Web site (www.pidj.com). Copyright 2010 by Lippincott Williams & Wilkins ISSN: 0891-3668/10/2905-0415 DOI: 10.1097/INF.0b013e3181da2171

nvasive fungal infections are an important cause of morbidity and mortality in patients with neutropenia who receive chemotherapy for cancer and following hematopoietic stem-cell transplantation (HSCT).1,2 Candida and Aspergillus are the most commonly identied pathogens in these patients. Fever without signs of localized fungal infection is the most common clinical presentation. As early, denitive diagnosis is difcult, empiric administration of antifungal agents has become a standard of practice in neutropenic patients who remain persistently febrile despite broad spectrum antibacterial therapy.3 As with adults, pediatric patients have hematologic and other malignancies that require chemotherapy and/or HSCT, which place them at risk for developing an invasive fungal infection.4 12 However, there is a paucity of randomized prospective double-blind clinical trials of antifungal therapy conducted in pediatric patients.13 Only 2 randomized clinical trials of empiric antifungal therapy that included pediatric patients have been reported; both studies found that a lipid formulation of amphotericin B was signicantly less toxic than conventional amphotericin B in persistently febrile neutropenic children.14,15 To our knowledge, there are no published reports of a randomized clinical trial of empiric antifungal therapy conducted exclusively in pediatric oncology patients. Caspofungin and liposomal amphotericin B (L-AmB) are antifungal agents with activity against Candida and Aspergillus spp.16 21; both have been studied as empiric antifungal therapy in predominantly adult febrile, neutropenic patients.22,23 We therefore investigated the safety and efcacy of caspofungin 50 mg/ m2/d and L-AmB 3 mg/kg/d as empiric therapy for suspected invasive fungal infections in pediatric patients (217 years) with persistent fever and neutropenia.

METHODS
This was a prospective, randomized, double-blind study conducted from June 2004 through September 2006 at 17 investigator sites in the United States and Europe. The protocol was
www.pidj.com |

The Pediatric Infectious Disease Journal Volume 29, Number 5, May 2010

415

Maertens et al

The Pediatric Infectious Disease Journal Volume 29, Number 5, May 2010

approved by the Ethical Review Committee at each investigator site. Written informed consent was obtained from the legal guardian of each patient before any study procedures were performed.

Study Population
Children between 2 and 17 years of age were eligible to participate if they had received chemotherapy for cancer or had undergone HSCT, had received parenteral broad-spectrum antibacterial therapy for at least 96 hours, and were both persistently neutropenic (absolute neutrophil count below 500 per cubic millimeter for at least 96 hours) and febrile (temperature above 38.0C within 24 hours before randomization). Patients were not eligible if they had an inadequately managed bacterial infection or documented invasive fungal infection at the time of enrollment. Patients also were not eligible if they had at the time of enrollment a bilirubin level 3 times the upper limit of normal (ULN), aspartate or alanine aminotransferase level 5 times ULN, platelet count 5000/mm3, or a requirement for rifampin, cyclosporine, or concomitant systemic antifungal therapy. Prior use of antifungal prophylaxis was permitted.

Study Design
After all inclusion and exclusion criteria were fullled, patients were assigned in a 2:1 ratio (according to a computergenerated randomization schedule) to receive either intravenous caspofungin (70 mg/m2 loading dose on Day 1, then 50 mg/m2 daily maximum 70 mg/d ) plus placebo corresponding to L-AmB, or L-AmB (3 mg/kg daily) plus placebo corresponding to caspofungin. As previously described,24 randomization was stratied by risk category: patients at high risk were dened as those who had undergone allogeneic bone marrow or peripheral blood stem-cell transplantation or had received chemotherapy for a relapse of acute leukemia (either acute myelogenous leukemia AML or acute lymphoblastic leukemia ALL ); all others were classied as low risk. Blinding was maintained by means of a double-blind, doubledummy procedure. Opaque covers were used to conceal the infusion bags and catheters used for infusions of L-AmB and the corresponding placebo, and the placebo infusions were colormatched to the corresponding active-drug infusions. Premedication was not allowed on day 1; infusion-related reactions could be treated at the discretion of the investigator, and premedication could be administered before subsequent doses. If study therapy was well tolerated but fever persisted for 5 or more days and the patients clinical condition deteriorated, the dosage could be increased (to 70 mg/m2/d for caspofungin and 5 mg/kg/d for L-AmB). The maximum dosage of caspofungin was 70 mg/d for both standard and high doses. The higher dose was maintained unless toxicity occurred, at which time the dosage could be reduced to the standard dose, or until study therapy was discontinued. For patients without evidence of documented invasive fungal infection, therapy continued until the resolution of neutropenia and up to 72 hours later; the maximum recommended duration was 28 days. For patients with documented invasive fungal infections, duration of study therapy was determined by the investigator but was recommended to continue for at least 14 days, and at least 7 days after resolution of neutropenia and of symptoms. An Adjudication Committee (composed of 3 outside experts not involved in the conduct of the trial) reviewed the blinded data from all cases of suspected invasive fungal infections and classied the infections (as proven, probable, or possible infections or as not an invasive fungal infection) on the basis of prespecied consensus criteria dened by the European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Mycoses Study Group.24 The Adjudication Committee members also determined the causal

pathogen, time of onset of infection, and response of baseline infections to study treatment, according to a prespecied protocol. Baseline invasive fungal infections were those present on or before day 2 of the study, and breakthrough infections those with an onset on day 3 or later. The assessments of the Adjudication Committee were nal, and only invasive fungal infections that the committee judged to be probable or proven were considered documented infections for the purpose of study analysis. The evaluation of safety and tolerability was the primary objective of the study and was assessed by statistical and clinical review of all safety events. Investigators monitored patients for clinical adverse events daily during the administration of study therapy and for 14 days thereafter. Infusion-related events (systemic symptoms during and 1 hour after infusion) were prospectively dened and evaluated daily. Laboratory studies were performed at the time of enrollment, twice weekly during study therapy, at the end of study therapy, and 2 weeks after the end of study therapy. The investigators assessed whether any clinical or laboratory adverse event was related to the study therapy. Efcacy assessments were based on a 5-part composite end point that has been used in previous studies of empiric antifungal therapy.22,23,2527 Treatment was considered successful if all 5 of the following criteria were met: successful treatment of any baseline invasive fungal infection (based on the Adjudication Committee assessment), absence of any breakthrough fungal infection during therapy or within 7 days after the completion of therapy (based on the Adjudication Committee assessment), survival for 7 days after the completion of therapy, no premature discontinuation of study therapy because of drug-related toxicity or lack of efcacy, and resolution of fever (dened as a temperature below 38C for at least 48 hours) during neutropenia. In addition, each component of the main end point was assessed. As different criteria for resolution of fever as a part of the composite end point in studies of empiric therapy may affect the overall response rate,27 the overall response analysis was repeated in an exploratory manner using (1) resolution of fever for 24 hours before the resolution of neutropenia, (2) resolution of fever at the 7-day post-therapy follow-up visit, and (3) exclusion of fever resolution from the composite end point.

Statistical Methods
The principal objective of this study was to estimate indices of safety, tolerability, and efcacy of caspofungin and L-AmB. The design and sample size were not intended to test specic hypotheses with regard to these indices, and therefore, the analyses displayed present point estimates and condence intervals (CIs) rather than P values. Safety and tolerability were assessed in all patients who received at least 1 dose of active study drug. The main safety evaluation was the proportion of patients with 1 or more clinical and/or laboratory drug-related adverse experience(s) during the study drug therapy period plus 14 days post-therapy. The proportion of patients and its respective 95% Clopper-Pearson exact condence interval (Proc-StatXact 5, Cytel Software Corporation, Cambridge, MA) were calculated for both treatment groups. Nephrotoxicity was dened as a doubling of the serum creatinine relative to baseline or an increase of 1 mg/dL in serum creatinine if the baseline value was above the upper limit of normal for age. The maximal increase in serum creatinine either while on study therapy or during the 2-week post-therapy follow-up period also was assessed relative to the baseline value. The main efcacy analysis was conducted in a modied intention-to-treat (MITT) population, comprising patients with persistent fever and neutropenia who received at least 1 complete dose of study therapy. The main efcacy evaluation was the 2010 Lippincott Williams & Wilkins

416

| www.pidj.com

The Pediatric Infectious Disease Journal Volume 29, Number 5, May 2010

Antifungal Therapy in Neutropenia

proportion of patients with a favorable overall response, dened as meeting each of the 5 response criteria described above. Observed proportions and their respective 95% Clopper-Pearson exact CIs were calculated for the overall response and for each of the 5 individual components. Observed proportions were also calculated within each treatment group by stratum (low-risk, high-risk), as well as combined across strata. In addition, the estimated proportion of patients with a favorable overall response was calculated using Cochran-Mantel-Haenszel weights to adjust for strata (lowrisk, high-risk), and their respective 95% CIs were computed using the normal approximation to the binomial distribution.28

due to possible inadequate clinical response in 3 patients: 1 (1.8%) in the caspofungin group and 2 (7.7%) in the L-AmB group.

Safety and Tolerability

The overall rate of drug-related clinical adverse events was similar in the 2 treatment arms (Table 1). Serious clinical adverse events that were considered to be drug related were reported in 1 (1.8%) caspofungin recipient (hypotension) and 3 (11.5%) L-AmB recipients (hyperbilirubinemia; circumoral edema; and angioneurotic edema with dyspnea, laryngospasm, and tachycardia); all 4 patients discontinued the intended course of therapy. One additional patient in the caspofungin group discontinued study therapy because of a drug-related (but nonserious) clinical adverse event (rash). Three patients died during the study: 2 (3.6%) in the caspofungin group and 1 (3.8%) in the L-AmB group. None of the fatal adverse events (pneumonia, septic shock, and respiratory failure) were considered to be drug related, and all 3 deaths occurred more than 7 days after the end of therapy. The most common drug-related clinical adverse events in both groups were fever and other systemic infusion-related events (Table 1). Severe infusion-related events occurred in 3 caspofungin recipients (fever, hypotension, and chest pain in 1 patient each) and 5 L-AmB recipients (fever in 3 patients, along with severe vomiting in 1 and severe chills, tachycardia, and tachypnea in another; perioral edema in 1 patient; and Quinckes edema (angioedema) plus tachycardia in 1 patient). The overall rate of drug-related laboratory adverse events was slightly lower in patients who received caspofungin than in those who received L-AmB (Table 1). Hypokalemia was the most

RESULTS Patient Population

Of 84 patients screened, 83 were randomized and 82 received study therapy. Among these 82 patients, 81 were included in the MITT population (Fig. 1). Baseline demographic characteristics were balanced between the 2 treatment groups (Table, Supplemental Digital Content 1, http://links.lww.com/INF/A429). More than 60% of patients in both groups had acute leukemia with similar proportions of AML and ALL in the 2 treatment groups and greater than 70% had an absolute neutrophil count 100/mm3. Previous antifungal prophylaxis, type of antifungal prophylaxis, and prior use of recombinant cytokines were also similar between the treatment groups. The mean duration of study therapy was 11.6 days (range 336 days) in the caspofungin group and 11.4 days (range 155 days) in the L-AmB group. The study drug dosage was increased to 70 mg/m2/d for caspofungin or 5 mg/kg/d for L-AmB

FIGURE 1. Consort chart of clinical trial. 2010 Lippincott Williams & Wilkins
www.pidj.com |

417

Maertens et al

The Pediatric Infectious Disease Journal Volume 29, Number 5, May 2010

common drug-related laboratory adverse event in both treatment groups (3.6% and 11.5% of caspofungin and L-AmB recipients, respectively). None of the laboratory adverse events was serious or led to discontinuation of study therapy. Nephrotoxicity occurred in 3 caspofungin recipients (5.5%) and 2 L-AmB recipients (8.0%). The maximal increases in serum creatinine above baseline value

were generally similar for the caspofungin and L-AmB treatment groups: mean (0.12 mg/dL versus 0.18 mg/dL, respectively) and median (0.1 mg/dL versus 0.1 mg/dL, respectively). Four patients (7.2%) in the caspofungin group and 3 patients (11.5%) in the L-AmB group had 0.25 mg/dL increase in serum creatinine relative to the baseline value.

Efficacy
TABLE 1. Safety Outcomes
Caspofungin (N 56) n (%) 95% CI L-AmB (N 26) n (%) 95% CI

Drug-related* adverse events Clinical 27 (48.2) 34.7 62.0 12 (46.2) 26.6 66.6 Laboratory 6 (10.7) 4.0 21.9 5 (19.2) 6.6 39.4 Most common drug-related adverse events Tachycardia 1 (1.8) 3 (11.5) Vomiting 1 (1.8) 2 (7.7) Chills 1 (1.8) 2 (7.7) Fever 16 (28.6) 6 (23.1) Headache 5 (8.9) 0 (0.0) Rash 5 (8.9) 0 (0.0) Hypokalemia 2 (3.6) 3 (11.5) Serious drug-related 1 (1.8) 3 (11.5) adverse events Discontinued due to 2 (3.6) 3 (11.5) drug-related adverse events 23 (41.1) 9 (34.6) Systemic infusionrelated adverse events Mild 18 (32.1) 4 (15.4) Moderate 9 (16.1) 3 (11.5) Severe 3 (5.4) 5 (19.2) Nephrotoxicity 3/55 (5.5) 2/25 (8.0)
*Determined by investigator to be possibly, probably, or definitely caused by the study drug. Incidence 6% in 1 or more treatment groups. Some patients had more than 1 type of systemic adverse event, and, therefore, may be classified in multiple categories of mild, moderate, or severe.

A favorable overall response was observed in 46.4% of patients who received caspofungin and 32.0% of those who received L-AmB; however, the 95% CIs for the treatment groups overlapped (Table 2). This study was not powered to detect statistically signicant differences between the treatment groups. Most patients in the study were enrolled into the low-risk category; in this group, the observed proportion of patients with a favorable overall response was similar across treatment groups (41.5% for caspofungin and 44.4% for L-AmB). Among high-risk patients, a favorable overall response was achieved in 9 (60%) of 15 caspofungin recipients and none (0%) of 7 L-AmB recipients. In both treatment groups, higher efcacy responses were noted in patients with AML (caspofungin and L-AmB, 77.8% versus 55.6%, respectively) than in patients with ALL (43.8% versus 28.6%), solid tumors (25.0% versus 0%), or other hematologic malignancies (16.7% versus 20.0%). The treatment groups were similar with respect to 3 efcacy components: successful treatment of baseline fungal infection, absence of breakthrough fungal infection, and survival for at least 7 days after completion of therapy (Table 2). Baseline fungal infection occurred in one patient: a 13-year-old white male with Ewing sarcoma who was randomized to receive caspofungin and who was subsequently diagnosed with probable Aspergillus pneumonia on day 1 of study therapy; the patient received 7 days of blinded study therapy with caspofungin, followed by 14 days of open-label caspofungin until he died because of worsening bilateral pneumonia. Breakthrough fungal infection also occurred in one patient: a 13-year-old male with relapsed AML who was randomized into the L-AmB group and subsequently diagnosed with probable Aspergillus pneumonia on day 8 of study therapy; L-AmB was discontinued after 55 days due to lack of efcacy and was replaced with open-label caspofungin and voriconazole for 9 days until the treatment was changed to L-AmB through the end of

TABLE 2. Efficacy Outcomes (Based on MITT Population)

Caspofungin (N n (%) Overall favorable response Adjusted for risk category Not adjusted for risk category Observed, according to risk category High risk Low risk Observed components of primary end point Successful treatment of baseline infection Absence of breakthrough fungal infection Survival to 7-d follow-up Treatment-related discontinuation No High risk Low risk Yes Lack of efficacy Drug toxicity Resolution of fever during neutropenia High risk Low risk 26 (46.6) 26 (46.4) 9/15 (60.0) 17/41 (41.5) 0/1 (0.0) 56/56 (100) 56/56 (100) 51/56 (91.1) 13/15 (86.7) 38/41 (92.7) 3 (5.4) 2 (3.6) 27/56 (48.2) 9/15 (60.0) 15/41 (36.6) (93.6 100) (93.6 100) (80.4 97.0) 56) 95% CI (33.559.6) (33.4 59.5) n (%) 8 (32.2) 8 (32.0) 0/7 (0.0) 8/18 (44.4) 24/25 (96.0) 25/25 (100) 21/25 (84.0) 3/7 (42.9) 18/18 (100) 1 (4.0) 3 (12.0) 9/25 (36.0) 1/7 (14.3) 7/18 (38.9) (79.7100) (86.3100) (63.9 95.5) L-AmB (N 25) 95% CI (13.9 50.5) (13.750.3)

(35.1 61.3)

(17.254.8)

418

| www.pidj.com

2010 Lippincott Williams & Wilkins

The Pediatric Infectious Disease Journal Volume 29, Number 5, May 2010

Antifungal Therapy in Neutropenia

TABLE 3. Favorable Overall Percent Response Rates Using Alternative Definitions of Fever Resolution
Afebrile Afebrile Without Afebrile for 48 h for 24 h Fever at 7 d While While Resolution Post-therapy Neutropenic* Neutropenic Component Caspofungin L-AmB 46.4% 32.0% 60.7% 52.0% 76.8% 60.0% 89.3% 84.0%

*Primary fever resolution endpoint as defined in protocol.

the follow-up period. All patients in both treatment groups survived for at least 7 days after completion of study therapy. Response rates for the remaining 2 components, successful completion of therapy (ie, no treatment-related discontinuations) and resolution of fever during neutropenia, were slightly higher among caspofungin recipients compared with L-AmB recipients, but the 95% condence intervals overlapped (Table 2). Premature discontinuation due to drug toxicity occurred in 3.6% of caspofungin recipients and in 12.0% of L-AmB recipients. Results of the exploratory analysis using alternate denitions of fever resolution demonstrate that both treatment groups have a progressive increase in the favorable overall response rate as the denition for fever resolution becomes less conservative (Table 3).

DISCUSSION
This is the rst reported prospective, randomized, doubleblind clinical trial of empiric antifungal therapy conducted exclusively in pediatric patients. The design was very similar to the previous multicenter, double-blind, randomized study that compared caspofungin and L-AmB as empiric antifungal therapy in adult patients with persistent fever and neutropenia.23 Similarities in design included the key inclusion and exclusion criteria, the clinical and laboratory measurements for safety, the efcacy assessment based on a 5-part composite end point and the use of an independent Adjudication Committee to review all cases of suspected fungal infection. The caspofungin dosage was chosen to achieve plasma exposures comparable to those of adults.29 As the plasma exposure of L-AmB 3 mg/kg is similar between adult and pediatric patients, this dosage was the same as that given in the previous adult study. L-AmB 3 mg/kg/d was found to be similar in efcacy but safer than 10 mg/kg/d in the primary treatment of invasive aspergillosis.30 In this study, the rates of drug-related clinical and laboratory adverse events were similar in pediatric patients treated with caspofungin (48.2% and 10.7%) and those treated with L-AmB (46.2% and 19.2%) and are consistent with the rates reported in adults who received caspofungin as empiric antifungal therapy (47.0% and 22.5%).23 The safety prole in this study is comparable to those of earlier open label studies of caspofungin in children.31,32 In contrast to the adult study, where caspofungin was associated with less nephrotoxicity than L-AmB, the rates of nephrotoxicity in this study were similar for the caspofungin and L-AmB treatment groups. Similar rates of nephrotoxicity have been reported for L-AmB (11%) and amphotericin B colloidal dispersion (ABCD) (12%) in children with fever and neutropenia.14,15 This result raises the possibility that amphotericin Binduced nephrotoxicity may not be as clinically apparent in children compared with adults who receive L-AmB. The overall rate of systemic infusion-related events was also similar between the treatment groups; however, the majority of these events were mild in caspofungin recipients while the majority of infusion-related 2010 Lippincott Williams & Wilkins

events were severe in L-AmB recipients. In both treatment groups, infusion-related fever was less common (23.2% and 26.9%) than previously reported for ABCD in children (74%).15 Previous studies in adult patients reported an uncommon but debilitating form of severe acute infusion-related toxicity in patients receiving 33,34 L-AmB. On the other hand, while caspofungin has the potential of inducing histamine release,35 histamine-related toxicity is seldom observed in most studies. Empiric antifungal therapy with caspofungin was associated with a favorable overall response rate (46.4%) similar to that observed for L-AmB (32.0%). These results are similar to those of the previous adult study, where 33.9% of caspofungin recipients and 33.7% of L-AmB recipients had a favorable overall response. Higher response rates have been reported for L-AmB (63%) and ABCD (69%) in children with fever and neutropenia14,15; however, these studies used slightly different composite endpoints that included fever resolution but did not require it to occur during neutropenia. Because fever is neither a sensitive nor a specic indicator of an IFI, Segal et al36 propose removing fever resolution from the primary end point in empiric therapy trials. This modied end point denition gives favorable overall response rates of 89% for caspofungin and 84% for L-AmB in the current study. The main limitation of this study is the total number of patients enrolled, which was much smaller than in the previous study in adults (82 versus 1111). As the objective of the study was to estimate parameters of safety, tolerability, and efcacy of caspofungin and L-AmB, sample size was not intended to test specic hypotheses with regard to these parameters. Thus, the analyses displayed present point estimates and condence intervals (CIs) rather than p-values. An additional potential limitation pertains to the schedule of laboratory safety monitoring. Although clinical adverse events were assessed daily while on study therapy and for 14 days thereafter, laboratory assessments were limited to twice-weekly sampling while on study therapy as well as an assessment on the last day of study therapy and at the 14-day post-therapy follow-up visit. This approach was chosen to limit excessive blood collection in this young, anemic patient population. Of note, a similar approach was employed in other caspofungin pediatric studies29,32 as well as the study of caspofungin for empiric antifungal therapy in neutropenic adults.23 Despite these limitations, the results of this study suggest that caspofungin and L-AmB are comparable in safety, tolerability, and efcacy when used as empiric therapy in pediatric patients (217 years) with persistent fever and neutropenia. Finally, as there are few randomized controlled clinical trials of antifungal therapy dedicated exclusively to pediatric patients, this report demonstrates the feasibility of conducting such studies to advance our understanding of the treatment and prevention of invasive mycoses in children with cancer.

ACKNOWLEDGMENTS
The authors thank all the patients and their caregivers who participated in this study, as well as all members of the Protocol 044 Study Group. The authors also thank Alfred Saah, Hedy Teppler, and Anne Henry for their contributions to the design and conduct of the study. Funding for this study was provided in part by Merck & Co., Inc. The industrial sponsor provided assistance with study design, data acquisition, and statistical analyses. Authors had full access to data and data analysis. Members of the Caspofungin Pediatric Study Group study group: Investigators. Belgium: J. Maertens; Germany: F. Berthold, A. Groll, T. Lehrnbecher, A. Simon; Spain: V. Castel Sanchez, P. Garcia Miguel, L. Madero-Lopez, J. Sanchez de Toledo; United
www.pidj.com |

419

Maertens et al

The Pediatric Infectious Disease Journal Volume 29, Number 5, May 2010

States: P. Flynn, M. Green, H. Jafri, J. Nania, M. Pulsipher, A. Reilly, N. Seibel, R. Yogev. Adjudication Committee. Ben E. de Pauw, Carola A. S. Arndt, and Thomas J. Walsh. REFERENCES
1. Sipsas NV, Bodey GP, Kontoyiannis DP. Perspectives for the management of febrile neutropenic patients with cancer in the 21st century. Cancer. 2005;103:11031113. 2. Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med. 2006;173:707717. 3. Hughes WT, Armstrong D, Bodey GP, et al. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730 751. 4. Groll AH, Kurz M, Schneider W, et al. Five-year-survey of invasive aspergillosis in a paediatric cancer centre. Epidemiology, management and long-term survival. Mycoses. 1999;42:431 442. 5. Abbasi S, Shenep JL, Hughes WT, et al. Aspergillosis in children with cancer: a 34-year experience. Clin Infect Dis. 1999;29:1210 1219. 6. Hovi L, Saarinen-Pihkala UM, Vettenranta K, et al. Invasive fungal infections in pediatric bone marrow transplant recipients: single center experience of 10 years. Bone Marrow Transplant. 2000;26:999 1004. 7. Krupova Y, Sejnova D, Dzatkova J, et al. Prospective study on fungemia in children with cancer: analysis of 35 cases and comparison with 130 fungemias in adults. Support Care Cancer. 2000;8:427 430. 8. Ridola V, Chachaty E, Raimondo G, et al. Candida infections in children treated with conventional chemotherapy for solid tumors (transplant recipients excluded): the Institut Gustave Roussy Pediatrics Department experience. Pediatr Blood Cancer. 2004;42:332337. 9. Mullen CA, Abd El-Baki H, Samir H, et al. Nonalbicans candida is the most common cause of candidemia in pediatric cancer patients. Support Care Cancer. 2003;11:321325. 10. Rosen GP, Nielsen K, Glenn S, et al. Invasive fungal infections in pediatric oncology patients: 11-year experience at a single institution. J Pediatr Hematol Oncol. 2005;27:135140. 11. Dvorak CC, Steinbach WJ, Brown JM, et al. Risks and outcomes of invasive fungal infections in pediatric patients undergoing allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2005;36:621 629. 12. Castagnola E, Cesaro S, Giacchino M, et al. Fungal infections in children with cancer: a prospective, multicenter surveillance study. Pediatr Infect Dis J. 2006;25:634 639. 13. Steinbach WJ, Walsh TJ. Mycoses in pediatric patients. Infect Dis Clin North Am. 2006;20:663 678. 14. Prentice HG, Hann IM, Herbrecht R, et al. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Br J Haematol. 1997;98:711 718. 15. Sandler ES, Mustafa MM, Tkaczewski I, et al. Use of amphotericin B colloidal dispersion in children. J Pediatr Hematol Oncol. 2000;22:242 246. 16. Deresinski SC, Stevens DA. Caspofungin. Clin Infect Dis. 2003;36:1445 1457. 17. Francis P, Lee JW, Hoffman A, et al. Efcacy of unilamellar liposomal amphotericin B in treatment of pulmonary aspergillosis in persistently granulocytopenic rabbits: the potential role of bronchoalveolar lavage D-mannitol and galactomannan as markers of infection. J Infect Dis. 1994;169:356 368. 18. Ng TT, Denning DW. Liposomal amphotericin B (AmBisome) therapy in invasive fungal infections. Evaluation of United Kingdom compassionate use data. Arch Intern Med. 1995;155:10931098.

19. Bartizal K, Gill CJ, Abruzzo GK, et al. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicrob Agents Chemother. 1997;41:2326 2332. 20. Abruzzo GK, Gill CJ, Flattery AM, et al. Efcacy of the echinocandin caspofungin against disseminated aspergillosis and candidiasis in cyclophosphamide-induced immunosuppressed mice. Antimicrob Agents Chemother. 2000;44:2310 2318. 21. Petraitiene R, Petraitis V, Groll AH, et al. Antifungal efcacy of caspofungin (MK-0991) in experimental pulmonary aspergillosis in persistently neutropenic rabbits: pharmacokinetics, drug disposition and relationship to galactomannan antigenemia. Antimicrob Agents Chemother. 2002;46:1223. 22. Walsh TJ, Finberg RW, Arndt C, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999;340:764 771. 23. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004;351:13911402. 24. Ascioglu S, Rex JH, de Pauw B, et al. Dening opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002;34:714. 25. Boogaerts M, Winston DJ, Bow EJ, et al. Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized, controlled trial. Ann Intern Med. 2001;135:412 422. 26. Winston DJ, Hathorn JW, Schuster MG, et al. A multicenter, randomized trial of uconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer. Am J Med. 2000;108:282289. 27. de Pauw BE, Sable CA, Walsh TJ, et al. Impact of alternate denitions of fever resolution on the composite endpoint in clinical trials of empirical antifungal therapy for neutropenic patients with persistent fever: analysis of results from the Caspofungin Empirical Therapy Study. Transpl Infect Dis. 2006;8:3137. 28. Cochran WG. Some methods for strengthening the common 2 tests. Biometrics. 1954;10:417 451. 29. Walsh TJ, Adamson PC, Seibel NL, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother. 2005;49:4536 4545. 30. Cornely OA, Maertens J, Bresnik M, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007;44:1289 1297. 31. Groll AH, Attarbaschi A, Schuster FR, et al. Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey. J Antimicrob Chemother. 2006;57:527535. 32. Zaoutis T, Jafri H, Huang L, et al. A prospective, multicenter study of caspofungin for the treatment of documented Candida or Aspergillus infections in pediatric patients. Pediatrics. 2009;123:877 884. 33. Johnson MD, Drew RH, Perfect JR. Chest discomfort associated with liposomal amphotericin B: report of three cases and review of the literature. Pharmacotherapy. 1998;18:10531061. 34. Roden MM, Nelson LD, Knudsen TA, et al. A triad of acute infusionrelated reactions associated with liposomal amphotericin B: analysis of clinical and epidemiological characteristics. Clin Infect Dis. 2003;36:1213 1220. 35. Cleary JD, Schwartz M, Rogers PD, et al. Effects of amphotericin B and caspofungin on histamine expression. Pharmacotherapy. 2003;23:966 973. 36. Segal BH, Herbrecht R, Stevens DA, et al. Dening responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria. Clin Infect Dis. 2008;47:674 683.

420

| www.pidj.com

2010 Lippincott Williams & Wilkins