Effects of Surgery Combined with Different Chemotherapy on Matrix Metalloproteinase-9 and Tissue Inhibitors of Metalloproteinase-1 in Children with Neuroblastoma

Abstract

Background. Neuroblastoma (NB) is a common extracranial malignancy in children and accounts for 15% of all cancer-related deaths in children, with the 5-year survival of patients in an advanced stage being lower than 40%. Preoperative adjuvant chemotherapy has been reported to facilitate surgical resection and improve the 2-year survival of patients. Objective. To analyze the efficacy of surgery plus different chemotherapy on children with NB and to investigate the correlation of matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinase-1 (TIMP-1) with chemotherapy efficacy. Methods. From April 2005 to May 2017, a total of 92 cases of NB treated in our hospital were assessed for eligibility and recruited. They were assigned at a ratio of 1: 1 to receive either CAV (cyclophosphamide + vincristine + adriamycin) (group A) and EP (etoposide + cisplatin) alternately or TOPO (topotecan) + CTX (cytoxan) + CiE (etoposide + cisplatin) + CPV (cyclophosphamide + pirarubicin + vincristine) (group B). The outcome measures include chemotherapy efficacy, surgical resection rates, complications, 2-year recurrence, and 2-year survival. The levels of NK cells, CD4+/CD8+ cells, MMP-9, TIMP-1, and urine catecholamine (VMA) in peripheral blood of patients before and after initial chemotherapy were determined to analyze the correlation of MMP-9, TIMP-1, and VMA with the efficacy of chemotherapy. Results. The two groups had similar efficacy (84.00% vs. 95.24%) and surgical resection rates (60.00% vs. 61.90%) after the initial chemotherapy ( $P>0.05$ ). Surgery for all eligible patients was successful after second chemotherapy. All eligible patients showed myelosuppression after chemotherapy, including 48 cases with stages I-II (52.17%) and 44 cases with stages III-IV (47.83%). The ratio of CD4+/CD8+ cells, MMP-9, TIMP-1, and VMA expression levels in peripheral blood of patients decreased ( $P<0.05$ ) after chemotherapy, and the ratio of CD4+/CD8+ cells was further reduced after surgery ( $P<0.05$ ), while natural killer (NK) cells levels increased ( $P<0.05$ ). However, intergroup differences were absent in the incidence of myelosuppression, CD4+/CD8+ cell ratio, NK cells, MMP-9, TIMP-1, and VMA expression levels ( $P>0.05$ ). MMP-9 and TIMP-1 were positively correlated with VMA ( $P<0.05$ ), and the expression levels of MMP-9 and TIMP-1 and VMA after chemotherapy were negatively correlated with chemotherapy efficiency ( $P<0.05$ ). Patients with high expressions of MMP-9, TIMP-1, and VMA were associated with lower 2-year survival versus those with low expressions ( $P<0.05$ ). Conclusion. Surgery plus chemotherapy for children with NB yields a promising clinical efficacy and a favorable surgical resection outcome. MMP-9 and TIMP-1 may be the potential biological indicators for chemotherapy efficiency and have a reference value for following surgical treatment of patients.