2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

antibiotics in the treatment of febrile neutropenia improves
patient outcomes. A meta-analysis of 13 studies revealed
that the use of CSFs in patients with established fever and
neutropenia reduces the amount of time spent in the hospital
and the neutrophil recovery period. Overall mortality
was not influenced by use of CSFs, but a marginally significant
decrease in infection-related mortality was noted. 15
Granulocyte Transfusions
Although the principal of granulocyte transfusions in
neutropenic patients with refractory infections is physiologically
sound, the data supporting this clinical practice have
been the subject of considerable controversy. Some early
randomized studies demonstrated a clinical benefit for the
PMN transfusion group compared with controls, 16 whereas
others showed no overall benefit although demonstrating
efficacy in certain subgroups of patients, 17 and still others
reported no benefit at all. 18 Furthermore, the administration
of granulocyte transfusions carries risks of alloimmunization
and respiratory distress.
Recent technical advances in the ability to collect substantially
larger numbers of PMNs per pheresis have opened
new potential for the therapeutic benefit of this adjunctive
modality. The use of G-CSF to mobilize granulocytes in
normal healthy donors has been shown to be safe and
effective, allowing for the collection of substantially more
PMNs per cycle of pheresis. 19 In addition to total number of
cells transfused, human leukocyte antigen (HLA) match is
also thought to be an important factor in the efficacy of
granulocyte transfusions. Given the technical advances in
G-CSF mobilization, WBC collection, and donor matching, a
randomized trial is warranted to investigate the use of
granulocyte transfusions in neutropenic patients with refractory
infections. However, the challenges posed by standardization
of collection methods, HLA matching, dose of
granulocytes, and type of patients enrolled are daunting to a
multicenter trial. Until such studies are available, selection
of candidate patients to receive granulocyte transfusions
must be made by an individual assessment of risk and
benefit.
Prophylactic Antimicrobial Therapy
Many clinical trials have focused on use of prophylactic
antibiotics to prevent infections in neutropenic patients. The
oral fluoroquinolone antibiotics have been investigated because
of their good bioavailability and broad activity against
aerobic bacteria. A meta-analysis of published randomized
controlled trials of quinolone prophylaxis (18 trials with
1,408 patients) found that quinolone prophylaxis substantially
reduced the incidence of gram-negative bacterial infections,
microbiologically documented infections, total
infections, and fevers, but did not alter the incidence of
gram-positive infections or infection-related deaths. 20 Two
recent distinct studies evaluating the use of prophylactic
oral levofloxacin (500 mg daily) in patients receiving chemotherapy
for either solid tumors or lymphoma 21 or hematologic
malignancies 22 both showed a reduction in documented
infections. Finally, a recent meta-analysis of antibiotic prophylaxis
in neutropenic patients with cancer (95 trials
performed between 1973 and 2004) concluded that antibiotic
prophylaxis (various antibiotic regimens) substantially decreased
the risk for death compared with placebo or no
568
treatment. 23 When trials that used quinolone prophylaxis
(52 trials) were separately analyzed, there was a substantial
reduction in the risk for all-cause mortality, as well as
infection-related mortality, fever, clinically documented infections,
and microbiologically documented infections. Although
these results are very encouraging, many of these
studies reported increasing rates of antimicrobial resistance
to quinolones. Thus, if quinolone prophylaxis is implemented,
vigilant monitoring of the incidence of bacteremia
(specifically gram-negative bacteremia) is mandatory to first
detect the loss of efficacy of fluoroquinolone prophylaxis.
The use of fluconazole as antifungal prophylaxis has been
conducted in adult patients with leukemia who have undergone
bone marrow transplantation. 24 Although a decrease in
fungal colonization and superficial infections was noted, a
reduction in systemic fungal infections and associated mortality
was identified only in the patients undergoing bone
marrow transplantation.
Augmentation of Mucocutaneous Barriers and
Commensal Gut Microbiota
Keratinocyte growth factor, a member of the family of
fibroblast growth factors, has been shown to reduced the
duration and severity of oral mucositis after intensive chemotherapy.
25 A preliminary analysis of blood-borne infections
showed a lower incidence among patients receiving
palifermin than among those receiving placebo. Future
investigations, however, are merited to assess the ability of
palifermin therapy to decrease the complications caused by
systemic infection.
Recent studies have shown that the GI microbiota plays a
crucial role in preventing overgrowth of pathogenic microbes—by
directly inhibiting the growth of specific pathogens
and/or by stimulation of GI mucosal effectors (e.g.,
antimicrobial proteins) that act to clear invading pathogens.
Although probiotic bacterial strains have been used to treat
inflammatory bowel disease, necrotizing enterocolitis, and
enteric infections human patients, no studies have been
performed in pediatric patients with cancer. The major
concern is that introduction of enteric bacteria may result in
dissemination of the introduced strain. The importance of
the microbiota in driving protective immune responses during
GI infection is best illustrated by the finding that
restoring signaling through innate immune receptors in
antibiotic-treated mice can protect from intestinal infections
(i.e., lipopolysaccharide activation of TLR4 or flagellin stimulation
of TLR5 to prevent vancomycin-resistant Enterococci
dissemination.). 26
Conclusion
ANDREW Y. KOH
Pediatric patients with cancer with prolonged neutropenia
have increased risk for severe, recurrent, or new bacterial
and fungal infections. Although prompt initiation of empirical
antibacterial antibiotics when the neutropenic patient
with cancer becomes febrile has lead to substantial improvement
in morbidity and mortality associated with bacterial
and fungal infections, infectious complications still persist.
Currently, appropriate administration of antibacterial and
antifungal antibiotics remains standard of care. Adjunctive
use of agents that promote healing of mucosal damage, use
of probiotics or prebiotics to reestablish gut microbiota
homeostasis, and granulocyte infusions offer promise, but
more definitive studies are necessary.