Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Review: Antifungal agents do not reduce mortality in neutropenia caused by chemotherapy or bone marrow transplantation

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ACP J Club. 2002 Nov-Dec;137:98. doi:10.7326/ACPJC-2002-137-3-098


Source Citation

Gøtzsche PC, Johansen HK. Routine versus selective antifungal administration for control of fungal infections in patients with cancer. Cochrane Database Syst Rev. 2002;(2):CD000026 (latest version 9 Jan 2002). [PubMed ID: 12076377]


Abstract

Question

In patients with cancer and neutropenia caused by chemotherapy or bone marrow transplantation (BMT), do antifungal agents reduce mortality?

Data sources

Studies were identified by searching 2 electronic databases, conference abstracts, and bibliographies and by contacting pharmaceutical manufacturers.

Study selection

Studies were selected if they were randomized controlled trials (RCTs) comparing antifungal agents with placebo or no treatment in patients with cancer and neutropenia caused by chemotherapy or BMT.

Data extraction

Data were extracted on patients, intervention, treatment duration, length of follow-up, randomization, blinding, and outcomes (deaths, invasive fungal infections [IFIs], colonization, and use of rescue drugs).

Main results

30 RCTs (4094 patients) were included. Patients had leukemia in 19 RCTs and BMT in 11 RCTs. Antifungal agents were given prophylactically in 27 RCTs and empirically in 3 RCTs. Treatment groups did not differ for mortality overall (Table) or when grouped by type of antifungal agent. Antifungal agents led to fewer infections overall; the treatment effect was seen for amphotericin, fluconazole, and itraconazole but not for ketoconazole or miconazole (Table).

Studies on colonization rates and use of rescue drugs were heterogeneous; antifungal agents led to lower rates of colonization and use of rescue drugs than did placebo or no treatment (Table).

Conclusions

In patients with cancer and neutropenia caused by chemotherapy or bone marrow transplantation, antifungal agents do not reduce mortality. Amphotericin, fluconazole, and itraconazole reduce invasive infection. Colonization and use of rescue drugs are reduced by antifungal agents.

Source of funding: No external funding.

For correspondence: Dr. P. Gøtzsche, Nordic Cochrane Centre, Copenhagen, Denmark. E-mail p.c.gotzsche@cochrane.dk.


Table. Antifungal agents vs placebo or no treatment for cancer with neutropenia*

Outcomes Antifungal agent Number of trials Weighted event rates RRR (95% CI) NNT (CI)
Antifungal agents Control
Death All 24 14.7% 15.4% 5% (−11 to 18) Not significant
Invasive infections All 26 4.2% 8.6% 50% (36 to 61) 23 (17 to 35)
Amphotericin 7 2.7% 7.5% 61% (24 to 80) 21 (13 to 63)
Fluconazole 8 4.3% 11% 61% (43 to 73) 15 (11 to 24)
Itraconazole 3 3.6% 7.2% 49% (4 to 73) 28 (15 to 334)
Miconazole 2 5.3% 10% 48% (−31 to 80) Not significant
RRI (CI) NNH
Ketoconazole 6 6.3% 4.6% 32% (−32 to 154) Not significant
RRR (CI) NNT (CI)
Colonization All 22 31% 47% 36% (21 to 47) 7 (5 to 12)†
Use of rescue drug All 20 44% 50% 12% (2 to 22) 19 (11 to 72)†

*Abbreviations defined in Glossary; RRI, RRR, NNT, NNH, and CI calculated from data in article using a fixed-effects model. Length of follow-up not reported.
†Statistically significant heterogeneity existed among trials; random-effects model was used.


Commentary

IFIs cause considerable morbidity and mortality in cancer patients treated with cytoreductive chemotherapy (1). The risk factors for IFI include fungal colonization (2), prolonged neutropenia (2), chemotherapy-induced muscosal damage (3), BMT (4), and graft-versus-host disease (GVHD) (5). As a result, clinicians have embraced several strategies to curtail these life-threatening infections: prophylactic, preemptive, and empiric use of antifungal agents, as well as environmental air control.

Gøtzsche and Johansen have exhaustively reviewed the effect of antifungal agents in neutropenic patients. They included a heterogeneous population of chemotherapy-induced neutropenic patients with cancer, as well as recipients of autologous and allogeneic marrow transplantation. By mixing different populations of patients with varying risks for IFI, the effect of the antifungal agent on the incidence and mortality of IFI could also have been masked. Allogeneic marrow transplant recipients have a greater potential for IFI than autologous recipients. In fact, the risk for IFI in the former group extends beyond the neutropenic period, after marrow engraftment, because of GVHD. As a result, prophylaxis may be extended for prolonged periods beyond the neutropenic phase. The authors did not consider this key issue and evaluated heterogeneous populations, which may have influenced IFI risk and mortality, although they were cognizant of other sources of bias. As they acknowledge, early rescue therapy with a parenteral antifungal agent (usually an amphotericin B compound) may have diminished mortality.

A more perplexing issue is why 27 prophylactic and 3 empiric trials were combined. Most prophylactic trials use oral antifungal agents (22/27 trials in this review) because of ease of administration, while empiric rescue therapy is administered intravenously.

Antifungal therapy most certainly reduces the incidence of IFI. However, its effect on mortality requires a better understanding of which groups stand to benefit the most.

Coleman Rotstein, MD
McMaster University
Hamilton, Ontario, Canada


References

1. Bow EJ. Invasive fungal infection in patients receiving intensive cytotoxic chemotherapy for cancer. Br J Haematol. 1998;101 Suppl 1:1-4. [PubMed ID: 9607733]

2. Rotstein C, Bow EJ, Laverdiere M, et al. Randomized placebo-controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. Clin Infect Dis. 1999;28:331-40. [PubMed ID: 10064252]

3. Bow EJ, Loewn R, Cheang MS, Schacter B. Invasive fungal disease in adults undergoing remission-induction therapy for acute myeloid leukemia: the pathogenic role of the antileukemic regimen. Clin Infect Dis. 1995;21:361-9. [PubMed ID: 8562745]

4. Goodrich JM, Reed EC, Mori M, et al. Clinical features and analysis of risk factors for invasive candidal infection after marrow transplantation. J Infect Dis. 1991;164:731-40. [PubMed ID: 1894935]

5. Meyers JD. Fungal infections in bone marrow transplant patients. Semin Oncol. 1990(3 Suppl 6);17:10-3. [PubMed ID: 2353204]