Abstract
Background: Cytoreductive surgery in combination with
hyperthermic intraperitoneal chemotherapy has been established as a
novel treatment approach for peritoneal sarcomatosis. Despite promising
clinical reports, there is still a lack of knowledge regarding optimal
drug usage and local effects. Therefore, we intended to establish a
murine animal model for further evaluation.
Procedure: Alveolar rhabdomyosarcoma cells were
xenotransplanted into NOD/LtSz-scid IL2Rγnullmice (n=100). The mice
received a continuous intraperitoneal lavage with isotonic saline
solution as control- or with cisplatin (30 or 60
mg/m2) as treatment group for 60 minutes at 37 or
42 °C (6 subgroups, each n=16). Tumor spread was documented by an
adapted peritoneal cancer index and MRI (n=4). Tumor and tissue samples,
harvested at the end of the perfusion, were evaluated regarding
morphology, proliferation and apoptosis (H&E-, Ki-67-, Cleaved Caspase
3-staining, TUNEL-assay).
Results: Extensive peritoneal sarcomatosis in over 91% of the
cases was observed. HIPEC was feasible without acute side effects. Ki-67
staining revealed concentration- or temperature-dependent effects of
cisplatin-based HIPEC on the tumors. While Cleaved Caspase-3 showed only
sporadic apoptotic effects. TUNEL-assay detected concentration- or
temperature-dependent apoptotic effects at the outer tumor surface. MRI
scans confirmed the observed tumor dissemination.
Conclusion: This is the first animal model for evaluation of
HIPEC in pediatric RMS in mice. Cisplatin-based HIPEC had early effects
on the proliferation whereas circumscribed apoptotic effects could be
detected at the tumor surface. This model allows further insights on the
possible efficiency of HIPEC in RMS. Further studies using other drug
combinations and treatment will follow.