Enhanced antitumor effect of combined-modality treatment using convection-enhanced delivery of hydrophilic nitrosourea with irradiation or systemic administration of temozolomide in intracranial brain tumor xenografts

Objective: Convection-enhanced delivery (CED) is a local infusion technique that delivers chemotherapeutic agents directly to the central nervous system, circumventing the blood-brain barrier and reducing systemic side effects. We previously reported the safety and efficacy of CED of ACNU (nimustine hydrochloride: 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1- nitrosourea hydrochloride), a hydrophilic nitrosourea, in rat brain tumor models. This study evaluated the efficacy of combined-modality treatments using CED of ACNU with irradiation or systemic administration of temozolomide. Methods: Antitumor efficacy and toxicity of the treatment were evaluated using rat 9L intracranial brain tumor models. Results: Combined treatment using CED of ACNU with irradiation produced significantly longer survival time than each treatment alone (versus CED: p<0.001, versus irradiation: p<0.05, log-rank test) or systemic administration of ACNU with irradiation (p<0.001). Long-term survival (120 days) and eradication of tumor occurred only in this combined-treatment group. We also showed that CED of ACNU plus systemic administration of temozolomide significantly enhanced survival rate compared with each treatment alone (versus CED: p<0.001, versus systemic temozolomide: p<0.05). Discussion: Multimodality treatment using CED of ACNU, radiotherapy and systemic chemotherapy with temozolomide is a promising strategy for treatment of brain tumors.