BACKGROUND: Intensive cytotoxic chemotherapy for people with cancer can cause severe and prolonged cytopenia, especially neutropenia, a critical condition that is potentially life-threatening. When manifested by fever and neutropenia, it is called febrile neutropenia (FN). Invasive fungal disease (IFD) is one of the serious aetiologies of chemotherapy-induced FN. In pre-emptive therapy, physicians only initiate antifungal therapy when an invasive fungal infection is detected by a diagnostic test. Compared to empirical antifungal therapy, pre-emptive therapy may reduce the use of antifungal agents and associated adverse effects, but may increase mortality. The benefits and harms associated with the two treatment strategies have yet to be determined. OBJECTIVES: To assess the relative efficacy, safety, and impact on antifungal agent use of pre-emptive versus empirical antifungal therapy in people with cancer who have febrile neutropenia.
SEARCH METHODS: We searched CENTRAL, MEDLINE Ovid, Embase Ovid, and ClinicalTrials.gov to October 2021.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared pre-emptive antifungal therapy with empirical antifungal therapy for people with cancer.
DATA COLLECTION AND ANALYSIS: We identified 2257 records from the databases and handsearching. After removing duplicates, screening titles and abstracts, and reviewing full-text reports, we included seven studies in the review. We evaluated the effects on all-cause mortality, mortality ascribed to fungal infection, proportion of antifungal agent use (other than prophylactic use), duration of antifungal use (days), invasive fungal infection detection, and adverse effects for the comparison of pre-emptive versus empirical antifungal therapy. We presented the overall certainty of the evidence for each outcome according to the GRADE approach.
MAIN RESULTS: This review includes 1480 participants from seven randomised controlled trials. Included studies only enroled participants at high risk of FN (e.g. people with haematological malignancy); none of them included participants at low risk (e.g. people with solid tumours). Low-certainty evidence suggests there may be little to no difference between pre-emptive and empirical antifungal treatment for all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.72 to 1.30; absolute effect, reduced by 3/1000); and for mortality ascribed to fungal infection (RR 0.92, 95% CI 0.45 to 1.89; absolute effect, reduced by 2/1000). Pre-emptive therapy may decrease the proportion of antifungal agent used more than empirical therapy (other than prophylactic use; RR 0.71, 95% CI 0.47 to 1.05; absolute effect, reduced by 125/1000; very low-certainty evidence). Pre-emptive therapy may reduce the duration of antifungal use more than empirical treatment (mean difference (MD) -3.52 days, 95% CI -6.99 to -0.06, very low-certainty evidence). Pre-emptive therapy may increase invasive fungal infection detection compared to empirical treatment (RR 1.70, 95% CI 0.71 to 4.05; absolute effect, increased by 43/1000; very low-certainty evidence). Although we were unable to pool adverse events in a meta-analysis, there seemed to be no apparent difference in the frequency or severity of adverse events between groups. Due to the nature of the intervention, none of the seven RCTs could blind participants and personnel related to performance bias. We identified considerable clinical and statistical heterogeneity, which reduced the certainty of the evidence for each outcome. However, the two mortality outcomes had less statistical heterogeneity than other outcomes.
AUTHORS' CONCLUSIONS: For people with cancer who are at high-risk of febrile neutropenia, pre-emptive antifungal therapy may reduce the duration and rate of use of antifungal agents compared to empirical therapy, without increasing over-all and IFD-related mortality; but the evidence regarding invasive fungal infection detection and adverse events was inconsistent and uncertain.
ANTECEDENTES: Las Infecciones Fúngicas Invasivas (IFIs) causan morbilidad y mortalidad significativas en los pacientes con cáncer hematológico con alto riesgo de neutropenia febril (NF). Estos pacientes por lo tanto con frecuencia reciben terapia antifúngica empírica. La terapia antifúngica anticipada con prueba diagnóstica ha sido evaluada como una estrategia de tratamiento alternativa en estos pacientes.
MÉTODOS: Se realizó una búsqueda electrónica para literatura que comparaba estrategias antifúngicas empíricas versus anticipadas en NF entre pacientes adultos con cáncer hematológico. Se revisaron sistemáticamente 9 estudios, incluyendo ensayos controlados aleatorizados, estudios de cohorte, y estudios de viabilidad. Se utilizaron modelos de efectos aleatorios y fijos para generar estimaciones del riesgo relativo combinado de detección de IFI, mortalidad relacionada a IFI, mortalidad general, y tasas y duración de la terapia antifúngica. La heterogeneidad fue medida con Cochran's Q test, I2 statistic y T2 entre estudios. Incorporando estos parámetros y los costos directos de las drogas y pruebas diagnósticas, se construyó un modelo de costos comparativo para las dos estrategias. Se realizó un análisis de sensibilidad probabilística de estimación combinada y análisis de sensibilidad en un sentido de otros parámetros clave con estimaciones inciertas.
RESULTADOS: Nueve estudios publicados cumplieron con los criterios de inclusión. Comparadas con la terapia antifúngica empírica, las estrategias anticipadas se asociaron a una exposición antifúngica significativamente menor (RR 0.49, IC 95% 0.27-0.85) y duración sin un incremento en la mortalidad relacionada a IFI (RR 0.82, IC 95% 0.36-1.87) o mortalidad general (RR 0.95, IC 95% 0.46-1.99). La estrategia anticipada costó $324 menos (intervalo de credibilidad del 95% -$291.88 a $418.65 de la anticipada comparada con la empírica) que el enfoque empírico por episodio de NF. Sin embargo, la diferencia de costo estuvo influenciada por cambios relativamente pequeños en los costos de la terapia antifúngica y de las pruebas diagnósticas.
CONCLUSIONES: Comparada con la terapia antifúngica empírica, la terapia antifúngica anticipada en pacientes con alto riesgo de NF puede disminuir el uso de antifúngicos sin incrementar la mortalidad. En la literatura actual, se demostró un estado de equilibrio económico entre las estrategias de tratamiento antifúngico empírico y anticipado diagnóstico-dirigido, influenciado por pequeños cambios en el costo de la terapia antifúngica y pruebas diagnósticas. Este trabajo enfatiza la necesidad de optimización de las estrategias diagnósticas fúngicas existentes, desarrollo de estrategias diagnósticas más eficientes, y antifúngicos menos tóxicos y más costo-efectivos.
Intensive cytotoxic chemotherapy for people with cancer can cause severe and prolonged cytopenia, especially neutropenia, a critical condition that is potentially life-threatening. When manifested by fever and neutropenia, it is called febrile neutropenia (FN). Invasive fungal disease (IFD) is one of the serious aetiologies of chemotherapy-induced FN. In pre-emptive therapy, physicians only initiate antifungal therapy when an invasive fungal infection is detected by a diagnostic test. Compared to empirical antifungal therapy, pre-emptive therapy may reduce the use of antifungal agents and associated adverse effects, but may increase mortality. The benefits and harms associated with the two treatment strategies have yet to be determined.
OBJECTIVES:
To assess the relative efficacy, safety, and impact on antifungal agent use of pre-emptive versus empirical antifungal therapy in people with cancer who have febrile neutropenia.
SEARCH METHODS:
We searched CENTRAL, MEDLINE Ovid, Embase Ovid, and ClinicalTrials.gov to October 2021.
SELECTION CRITERIA:
We included randomised controlled trials (RCTs) that compared pre-emptive antifungal therapy with empirical antifungal therapy for people with cancer.
DATA COLLECTION AND ANALYSIS:
We identified 2257 records from the databases and handsearching. After removing duplicates, screening titles and abstracts, and reviewing full-text reports, we included seven studies in the review. We evaluated the effects on all-cause mortality, mortality ascribed to fungal infection, proportion of antifungal agent use (other than prophylactic use), duration of antifungal use (days), invasive fungal infection detection, and adverse effects for the comparison of pre-emptive versus empirical antifungal therapy. We presented the overall certainty of the evidence for each outcome according to the GRADE approach.
MAIN RESULTS:
This review includes 1480 participants from seven randomised controlled trials. Included studies only enroled participants at high risk of FN (e.g. people with haematological malignancy); none of them included participants at low risk (e.g. people with solid tumours). Low-certainty evidence suggests there may be little to no difference between pre-emptive and empirical antifungal treatment for all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.72 to 1.30; absolute effect, reduced by 3/1000); and for mortality ascribed to fungal infection (RR 0.92, 95% CI 0.45 to 1.89; absolute effect, reduced by 2/1000). Pre-emptive therapy may decrease the proportion of antifungal agent used more than empirical therapy (other than prophylactic use; RR 0.71, 95% CI 0.47 to 1.05; absolute effect, reduced by 125/1000; very low-certainty evidence). Pre-emptive therapy may reduce the duration of antifungal use more than empirical treatment (mean difference (MD) -3.52 days, 95% CI -6.99 to -0.06, very low-certainty evidence). Pre-emptive therapy may increase invasive fungal infection detection compared to empirical treatment (RR 1.70, 95% CI 0.71 to 4.05; absolute effect, increased by 43/1000; very low-certainty evidence). Although we were unable to pool adverse events in a meta-analysis, there seemed to be no apparent difference in the frequency or severity of adverse events between groups. Due to the nature of the intervention, none of the seven RCTs could blind participants and personnel related to performance bias. We identified considerable clinical and statistical heterogeneity, which reduced the certainty of the evidence for each outcome. However, the two mortality outcomes had less statistical heterogeneity than other outcomes.
AUTHORS' CONCLUSIONS:
For people with cancer who are at high-risk of febrile neutropenia, pre-emptive antifungal therapy may reduce the duration and rate of use of antifungal agents compared to empirical therapy, without increasing over-all and IFD-related mortality; but the evidence regarding invasive fungal infection detection and adverse events was inconsistent and uncertain.
Pregunta de la revisión sistemática»Revisión sistemática de intervenciones
