Cullen, M.H., Billingham, L.J., Gaunt, C.H., & Steven, N.M. (2007). Rational selection of patients for antibacterial prophylaxis after chemotherapy. Journal of Clinical Oncology, 25, 4821–4828.
Adult patients with cancer receiving cyclic chemotherapy for solid tumors or lymphoma who were at risk for temporary, severe neutropenia (absolute neutrophil count [ANC] < 500/mm³) were treated with oral levofloxacin 500 mg or matching placebo daily for seven days during the expected neutropenic period. Treatment began on day 5 for regimens associated with early onset of neutropenia (e.g., docetaxel), day 8 for 14-day and 21-day cycles, and day 15 for 28-day cycles.
Patients were on study for a mean of 4.4 cycles of chemotherapy, with 45% of patients completing six cycles.
784 patients were randomly assigned to the placebo arm and received 3,459 cycles of chemotherapy (mean = 4.4 cycles per patient).
Random assignment of patients in the SIGNIFICANT trial was stratified by age (younger than age 40, 40–59, and 60 years of age and older) and cancer type (breast, testicular, small cell lung, Hodgkin disease, non-Hodgkin lymphoma [NHL], and others).
1,565 adults starting chemotherapy for solid tumors or lymphomas; eligible regimens were known to be associated with a risk of neutropenia (ANC < 500/mm³), but were not routinely given with granulocyte–colony-stimulating factor (G-CSF) support. Many different types of cancer were included.
60 oncology centers in the United Kingdom.
The study was a prospective, multicenter, randomized, double-blind, placebo-controlled trial with secondary univariate and multivariate analysis.
119 of 784 (15.2%) control group participants had at least one FE during chemotherapy.
Treatment benefit of quinolone prophylaxis was present across all cycles.
As reported in a 2005 article by the authors, the per-patient FE rate was 10.8% (84 of 781) for patients receiving levofloxacin compared with 15.2% for patients receiving placebo (119 of 784), giving a statistically significant reduction in the risk of FE (odds ratio = 0.67; 95% confidence interval [0.5, 0.91]; p =0.009).
For the first cycle only, the per-patient FE rate was 3.5% in patients receiving levofloxacin compared with 7.9% in controls (odds ratio = 0.42; 95% confidence interval [0.26, 0.66]; p =0.0001), whereas for non–first cycles, the per-patient FE rate was 7.8% (61 of 781) and 9.8% (77 of 784), respectively (odds ratio = 0.78; 95% confidence interval [0.55, 1.11]; p = 0.16).
Per-cycle FE rates in cycle 2 and cycles 2–6 indicate that prophylactic benefit is gained in the small number of patients who experience an FE in cycle 1, but not in the much larger group of patients who do not experience an FE in cycle 1.
The data suggest that the benefit of antibiotics is greatest in those who experience an FE in cycle 1 because they are at higher risk of developing an FE in subsequent cycles compared with patients who do not develop an FE in cycle 1.