Discussion
In this study, we evaluated the efficacy of the IREC therapy in 43
patients with refractory or relapsed neuroblastoma; a high disease
control rate of 88% (38 of 43) was observed in this cohort. This is
consistent with the reported in a previous report by Inoue et
al. , in which all five patients with refractory or relapsed
neuroblastoma achieved disease control with IREC
therapy8. Although a direct comparison is not
appropriate because of the large difference in patient characteristics
among the cohorts, the IREC therapy achieved a promising disease control
rate, similar to that of other reported salvage therapies for
neuroblastoma (ICE, 82%6; TOPO-CY,
62%7; Irinotecan alone, 77%4; and
irinotecan + temozolomide, 75%5). The IREC regimen
would serve as a promising treatment option for patients with refractory
or relapsed neuroblastoma.
Grade IV hematological toxicity after IREC treatment was observed in
97% of patients; however, it was successfully managed with G-CSF and
transfusion therapy, and no deaths due to infection were recorded. The
main nonhematological toxicity was FN (23%); other ≥ grade III
nonhematological toxicities were observed in only 6% of cases. The
incidence of bloodstream infection (BSI) (6 of 43 patients and 6.1% of
all cycles) was lower than that reported with ICE
(26%)6 and was similar to that of irinotecan with
temozolomide (3 of 47 patients)5. Our results suggest
that IREC is a relatively safe chemotherapy regimen for patients with
refractory or relapsed neuroblastoma.
Irinotecan is hydrolyzed by carboxylesterase to its active metabolite
SN-38, which is then metabolized by UGT1A1 to the non-toxic glucuronide
SN-38G. The presence of UGT1A1 gene polymorphisms has been shown
to decrease the metabolism of SN-38 and is associated with a higher
incidence of neutropenia and diarrhea, which are major side effects of
irinotecan treatment9. However, the CDE11 regimen
including irinotecan for adult diffuse large B cell lymphoma was shown
to confer a better prognosis in cases with UGT1A1*6polymorphisms15. In the present study, patients withUGT1A1 gene polymorphisms showed an increased frequency of grade
IV neutropenia, but no increase in FN or BSI, compared to patients with
wild-type UGT1A1 . In contrast, patients with the UGT1A1gene polymorphisms showed significantly better 1-year OS and
progression-free survival rates than the wild type. Since the toxicity
of the IREC regimen was well managed in patients with the gene
polymorphisms, future clinical studies should assess whether higher
doses of irinotecan can improve the outcomes in patients in theUGT1A1 wild-type group.
In conclusion, this study suggests that IREC is also well-tolerated by
patients with UGT1A1 polymorphisms and could be an effective
second-line chemotherapy for refractory or relapsed neuroblastoma.