Trial Information

Clinical Study to Evaluate the Efficacy of Prophylactic Itraconazole in High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation for Pediatric Solid Tumors

With the advance of chemoradiotherapy, survival of patients, especially children, with
malignant disease has improved. However, prognosis is still poor with conventional
chemotherapy if patients have an advanced or high-risk tumor at diagnosis. Outcome in
advanced or high-risk pediatric solid tumor such as advanced neuroblastoma, high-risk brain
tumor, or recurrent pediatric solid tumor is still not satisfactory with conventional
chemotherapy. In this context, investigators have explored the possible efficacy of
high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) in patients
with high-risk or relapsed pediatric solid tumor. Efficacy of HDCT and ASCT has been well
demonstrated in high-risk neuroblastoma, high-risk brain tumor, and recurrent pediatric
solid tumors. Therefore, now, HSCT and ASCT is the most important treatment modality in the
treatment of a variety of pediatric solid tumors poorly responding to conventional
chemotherapy.

However, although HDCT and ASCT has improved the survival of patients with high-risk tumor,
a variety of clinical issues associated with HDCT and ASCT are present causing significant
morbidity and even mortality. The most frequent cause of morbidity associated with HDCT and
ASCT is infection. Once high-dose myeloablative chemotherapeutic agents are administered,
most hematopoietic cells in bone marrow die and prolonged marrow aplasia is unavoidable even
after autologous hematopoietic stem cells infusion because it takes time for infused stem
cells to reconstitute sufficient hematopoietic function. In addition, high-dose chemotherapy
results in severe gastrointestinal mucosal damage which facilitates bacterial and/or fungal
infection via damaged mucosal barrier. Therefore, infection is a major cause of morbidity
and mortality associated with HDCT and ASCT. Common pathogens associated with infection
during HDCT and ASCT are bacteria and fungi.

To reduce the chance of infection and therefore, to reduce the morbidity and mortality from
severe infection, various prophylactic antibiotics including antibacterial, antifungal, and
antiviral agents have been used according to standard guideline in allogeneic stem cell
transplantation. However, in autologous transplantation for solid tumor in which hematologic
recovery is rapid and immune suppression is less severe than allogeneic transplantation,
there is no standard guideline for the use of prophylactic antibiotics whereas infection is
the most important cause of morbidity. Standard guideline for the use of prophylactic
antifungal agent is also not available. While some institutes use anti-fungal agent
prophylactically, others use antifungal agent empirically only when neutropenic fever
persist despite of empirical use of antibacterial agents.

HDCT in pediatric solid tumor is generally more intensive, and therefore, usually cause more
severe mucositis than that in adult tumor. Severe mucositis facilitates fungal infection via
damaged mucosal barrier (mainly by Candida species). Therefore, use of prophylactic
anti-fungal agent may reduce the morbidity and mortality associated with HDCT and ASCT in
pediatric solid tumor. However, there is no randomized clinical study to evaluate the
efficacy of prophylactic use of anti-fungal agent to date.

Itraconazole is one of newly developed antifungal agents and many physicians started to use
itraconazole as first-line antifungal agent in the management of neutropenic fever in
immunocompromised patients. However, the efficacy of prophylactic itraconazole has not been
established in children with solid tumor, especially who receive HDCT and ASCT.

In this context, we are going to evaluate the efficacy of prophylactic use of itraconazole
in children with high-risk solid tumors during HDCT and ASCT. "Prophylactic" group will be
treated with itraconazole once ANC fall below 500/uL regardless of infection and "Empirical"
group will be treated with itraconazole only when high fever persists despite of treatment
with first-line anti-bacterial agents.