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Therapeutics

Itraconazole was as effective as amphotericin B for fever and neutropenia in cancer and led to fewer adverse events

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ACP J Club. 2002 Mar-Apr;136:58. doi:10.7326/ACPJC-2002-136-2-058


Source Citation

Boogaerts M, Winston DJ, Bow EJ, et al., and the Itraconazole Neutropenia Study Group. 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. Ann Intern Med. 2001 Sep 18;135:412-22. [PubMed ID: 11560454] (All 2002 articles were reviewed for relevancy, and abstracts were last revised in 2008.)


Abstract

Question

In patients with cancer, is itraconazole as effective and safe as amphotericin B for eliminating fever and neutropenia?

Design

Randomized (allocation concealed*), unblinded,* controlled trial with median follow-up of 7 to 8.5 days.

Setting

60 oncology centers in 10 countries.

Patients

384 patients (median age 48 y, 60% men) who were ≥ 18 years of age and were hospitalized for hematologic cancer with intensive myelosuppressive cytotoxic therapy and who had an absolute neutrophil count of ≤ 0.5 × 109 cells/L with an expected duration of ≥ 7 days and a body temperature > 38 °C that was unrelated to blood product transfusions or medications and that persisted despite ≥ 3 days of treatment with antibiotics. Exclusion criteria included severe liver or renal dysfunction, HIV seropositivity, proven invasive fungal infection, chest radiographs or computed tomographic scans suggestive of invasive fungal infection during previous neutropenic episodes, and a fever caused by bacterial or viral infection. Follow-up ranged from 94% to 100%.

Intervention

192 patients were allocated to intravenous itraconazole, 200 mg as a solution in water, infused every 12 hours for the first 48 hours and then daily from days 3 to 14. Itraconazole, 400 mg/d, was given orally from day 15 or replaced the intravenous dose from day 7, if tolerated. 192 patients were allocated to intravenous amphotericin B deoxycholate, 0.7 to 1.0 mg/kg of body weight/d in 5% dextrose water, infused over 4 to 6 hours for up to 28 days. Treatment was stopped if patients recovered from fever and neutropenia.

Main outcome measures

Treatment response (defined as recovery from fever [daily oral peak temperature < 38 °C] and neutropenia [absolute neutrophil count > 0.5 × 109 cells/L on ≥ 2 successive d]) and adverse events.

Main results

Analysis was by intention to treat. Itraconazole was as effective as amphotericin B for eliminating fever and neutropenia and led to fewer adverse events (Table).

Conclusion

In patients with cancer, itraconazole was as effective as amphotericin B for eliminating fever and neutropenia and led to fewer adverse events.

*See Glossary.

Source of funding: Janssen Research Foundation.

For correspondence: Dr. M. Boogaerts, University Hospital Gasthuisberg, Leuven, Belgium. E-mail marc.boogaerts@uz.kuleuven.ac.be.


Table. Itraconazole (Itracon) vs amphotericin B (Ampho B) for fever and neutropenia in cancer at end of treatment (median 7 to 8.5 d)†

Outcomes Itracon Ampho B RBI (95% CI) NNT (CI)
Treatment response 47% 38% 25% (−2.0 to 60) Not significant
RRR (CI)
Adverse events
Drug-related 4.7% 54% 91% (84 to 95) 3 (2 to 3)
Treatment withdrawal 19% 38% 51% (31 to 65) 6 (4 to 10)
Severe 19% 34% 43% (20 to 60) 7 (5 to 18)

†Abbreviations defined in Glossary; RBI, RRR, NNT, and CI calculated from data in article.


Commentary

Amphotericin B has been the standard drug used in practice and current treatment guidelines for antibiotic refractory febrile neutropenia (1, 2). The study by Boogaerts and colleagues, although limited by its open design and a slightly older amphotericin-B patient group, showed that empiric itraconazole was as effective as empiric amphotericin B for eliminating fever and neutropenia in patients with hematologic cancer.

Not surprisingly, this effect seems to be largely driven by the high rate of toxicity associated with amphotericin B. Over 3 times as many patients in the amphotericin-B group (21%) than in the itraconazole group (6.7%) had treatment failure because of toxicity-related discontinuation. Although a higher number of patients in the itraconazole group (11%) than in the amphotericin-B group (0.6%) changed antifungal regimens because of persistent fever (P = 0.001), groups did not differ for the number of breakthrough invasive fungal infections (2.8% in each group). However, no information is provided on differences between groups on types and outcomes of documented infections.

This study contributes to the literature on febrile neutropenia by suggesting that itraconazole is an effective and less toxic alternative to amphotericin B. Because newer and less toxic antifungal agents are substantially more expensive than amphotericin B deoxycholate, cost-effectiveness studies and local patterns of fungal epidemiology and resistance may be the most important factors driving treatment decisions for these patients (3).

Elizabeth J. Phillips, MD
Sunnybrook & Women’s College Health Sciences Centre
Toronto, Ontario, Canada


References

1. Bow EJ, Laverdiere M, Rotstein C. A systematic review of the efficacy of azoles and lipid-based formulations of amphotericin B as empirical antifungal therapy in persistently febrile neutropenic patients despite broad-spectrum anti-bacterial therapy. 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 2000.

2. Rex JH, Walsh TJ, Sobel JD, et al. Practice guidelines for the treatment of candidiasis. Clin Infect Dis. 2000;30:662-78. [PubMed ID: 10770728]

3. van Gool R. The cost of treating systemic fungal infections. Drugs. 2001;61(Suppl 1):49-56. [PubMed ID: 11219550]