Intravenous and Oral Itraconazole versus Intravenous Amphotericin B Deoxycholate as Empirical Antifungal Therapy for Persistent Fever in Neutropenic Patients with Cancer Who Are Receiving Broad-Spectrum Antibacterial Therapy

Intravenous and Oral Itraconazole versus Intravenous Amphotericin B Deoxycholate as Empirical Antifungal Therapy for Persistent Fever in Neutropenic Patients with Cancer Who Are Receiving Broad-Spectrum Antibacterial Therapy

A Randomized, Controlled Trial

Marc Boogaerts, MD, PhD;
Drew J. Winston, MD;
Eric J. Bow, MD;
Gary Garber, MD;
Annette C. Reboli, MD;
Anthony P. Schwarer, MD, FRACP;
Nicolas Novitzky, MD, PhD;
Angelika Boehme, MD;
Elisabeth Chwetzoff, MD;
Karel De Beule, RPh; and
the Itraconazole Neutropenia Study Group*

From University Hospital, Leuven, Belgium; University of California, Los Angeles, Medical Center, Los Angeles, California; University of Manitoba, Winnipeg, Manitoba, Canada; Ottawa Hospital–General Campus, University of Ottawa, Ottawa, Ontario, Canada; Robert Wood Johnson Medical School at Camden, Cooper Hospital, Camden, New Jersey; Alfred Hospital, Melbourne, Australia; Groote Schuur Hospital, Cape Town, South Africa; University Hospital, Frankfurt, Germany; Janssen Research Foundation, Issy-les-Moulineaux, France; and Janssen Research Foundation, Beerse, Belgium.

Abstract

Background: Amphotericin B deoxycholate is currently the standard empirical antifungal therapy in neutropenic patients with cancer who have persistent fever that does not respond to antibiotic therapy. However, this treatment often causes infusion-related and metabolic toxicities, which may be dose limiting.

Objective: To compare the efficacy and safety of itraconazole with those of amphotericin B as empirical antifungal therapy.

Design: An open randomized, controlled, multicenter trial, powered for equivalence.

Setting: 60 oncology centers in 10 countries.

Patients: 384 neutropenic patients with cancer who had persistent fever that did not respond to antibiotic therapy.

Intervention: Intravenous amphotericin B or intravenous itraconazole followed by oral itraconazole solution.

Measurements: Defervescence, breakthrough fungal infection, drug-related adverse events, and death.

Results: For itraconazole and amphotericin B, the median duration of therapy was 8.5 and 7 days and the median time to defervescence was 7 and 6 days, respectively. The intention-to-treat efficacy analysis of data from 360 patients showed response rates of 47% and 38% for itraconazole and amphotericin B, respectively (difference, 9.0 percentage points [95% CI, −0.8 to 19.5 percentage points]). Fewer drug-related adverse events occurred in the itraconazole group than the amphotericin B group (5% vs. 54% of patients; P = 0.001), and the rate of withdrawal because of toxicity was significantly lower with itraconazole (19% vs. 38%; P = 0.001). Significantly more amphotericin B recipients had nephrotoxicity (P < 0.001). Breakthrough fungal infections (5 patients in each group) and mortality rates (19 deaths in the itraconazole group and 25 deaths in the amphotericin B group) were similar. Sixty-five patients switched to oral itraconazole solution after receiving the intravenous formulation for a median of 9 days.

Conclusions: Itraconazole and amphotericin B have at least equivalent efficacy as empirical antifungal therapy in neutropenic patients with cancer. However, itraconazole is associated with significantly less toxicity.

*For other members of the Itraconazole Neutropenia Study Group, see the Appendix.

Article and Author Information

Grant Support: By Janssen Research Foundation, Beerse, Belgium.
Requests for Single Reprints: Marc Boogaerts, MD, PhD, Department of Hematology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium; e-mail, marc.boogaerts{at}uz.kuleuven.ac.be.
Current Author Addresses: Dr. Boogaerts: Department of Hematology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
Dr. Winston: Transplantation Biology Program, UCLA School of Medicine, Center for the Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095-1678.
Dr. Bow: Department of Internal Medicine, The University of Manitoba, Health Sciences Centre, 820 Sherbrooke Street, Winnipeg, Manitoba R3A 1R9, Canada.
Dr. Garber: Division of Infectious Disease, Ottawa Hospital-General Campus, University of Ottawa, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada.
Dr. Reboli: Department of Medicine, Robert Wood Johnson Medical School at Camden, Cooper Hospital, Education and Research Building, 401 Haddon Avenue, Room 270, Camden, NJ 08103.
Dr. Schwarer: Bone Marrow Transplant Programme, Alfred Hospital, Commercial Road, Melbourne, Victoria 3181, Australia.
Dr. Novitzky: Department of Haematology, Faculty of Health Sciences, University of Cape Town and Groote Schuur Hospital, Anzio Road, Observatory, Cape Town 7925, South Africa.
Dr. Boehme: Medical Clinic III, J.W. Goethe-University, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.
Dr. Chwetzoff: Bømloveien 16, 4027 Stavanger, Norway.
Dr. De Beule: Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Author Contributions: Conception and design: M. Boogaerts, D.J. Winston, E. Chwetzoff, K. De Beule.
Analysis and interpretation of the data: M. Boogaerts, D.J. Winston, E.J. Bow, G. Garber, A.P. Schwarer, N. Novitzky, K. De Beule.
Drafting of the article: M. Boogaerts, D.J. Winston, E.J. Bow, G. Garber, A.P. Schwarer, N. Novitzky, K. De Beule.
Critical revision of the article for important intellectual content: M. Boogaerts, D.J. Winston, E.J. Bow, G. Garber, A.C. Reboli, A.P. Schwarer, N. Novitzky, A. Boehme.
Final approval of the article: M. Boogaerts, D.J. Winston, E.J. Bow, G. Garber, A.C. Reboli, A.P. Schwarer, N. Novitzky, A. Boehme, E. Chwetzoff, K. De Beule.
Provision of study materials or patients: D.J. Winston, G. Garber, A.C. Reboli, A.P. Schwarer, N. Novitzky, A. Boehme.
Statistical expertise: E.J. Bow.
Collection and assembly of data: D.J. Winston.