Convection enhanced delivery of carboplatin in combination with radiotherapy for the treatment of brain tumors

Abstract

The purpose of this study was to further evaluate the therapeutic efficacy of convection enhanced delivery (CED) of carboplatin in combination with radiotherapy for treatment of the F98 rat glioma. Tumor cells were implanted stereotactically into the brains of syngeneic Fischer rats, and 13 or 17 d. later carboplatin (20 μg/10 μL) was administered by either CED over 30 min or by Alzet osmotic pumps (0.5 μg/μL/h for 168 h.) beginning at 7 d after tumor implantation. Rats were irradiated with a 15 Gy fractionated dose (5 Gy × 3) of 6 MV photons to the whole brain beginning on the day after drug administration. Other groups of rats received either carboplatin or X-irradiation alone. The tumor carboplatin concentration following CED of 20 μg in 10 μL was 10.4 μg/g, which was equal to that observed following i.v. administration of 100 mg/kg b.w. Rats bearing small tumors, treated with carboplatin and X-irradiation, had a mean survival time (MST) of 83.4 d following CED and 111.8 d following pump delivery with 40% of the latter surviving >180 d (i.e. cured) compared to 55.2 d for CED and 77.2 d. for pump delivery of carboplatin alone and 31.8 d and 24.2 d, respectively, for X-irradiated and untreated controls. There was no microscopic evidence of residual tumor in the brains of all long-term survivors. Not surprisingly, rats with large tumors had much shorter MSTs. Only modest increases in MSTs were observed in animals that received either oral administration or CED of temozolomide plus X-irradiation (23.2 d and 29.3 d) compared to X-irradiation alone. The present survival data, and those previously reported by us, are among the best ever obtained with the F98 glioma model. Initially, they could provide a platform for a Phase I clinical trial to evaluate the safety and potential therapeutic efficacy of CED of carboplatin in patients with recurrent glioblastomas, and ultimately a Phase II trial of carboplatin in combination with radiation therapy.

Convection-enhancement delivery of platinum-based drugs and LipoplatinTM to optimize the concomitant effect with radiotherapy in F98 glioma rat model

“…They reported an improvement of median survival time (MeST) or even cure of glioma bearing rats when combined with radiation therapy [12][13][14][15][16][17]. Additionally, a phase I clinical trial showed that it was safe and feasible to deliver carboplatin by CED to treat glioblastoma [18].…”

Development of binary technologies of radiotherapy of malignant neoplasms: condition and problems

“…Однако последующие ýксперименты, прове-денные на фотонах 6 МВ линейного ускорителя, показали практически одинаковые результаты с облучением моноýнергетическими фотонами 78,8 кýВ синхротрона [31,33,34]. На наш взгляд, обычный линейный ускоритель можно исполь-зовать в качестве источника излучения для ýтой технологии, что позволит значительно расши-рить клиническую применимость такого подхода по сравнению с синхротронной лучевой терапи-ей, которая может быть осуществлена только на очень небольшом количестве специализирован-ных облучательных установках.…”

“…В дальнейших исследованиях PAT-Plat рас-сматриваются ýффективные средства доставки платиносодержащих препаратов в опухоль -ме-тод CED [33,34] и фармакологические формы [39,40]. Метод CED предлагается также и для до-ставки борсодержащих препаратов для НÇТ [41,42].…”

“…Метод CED предлагается также и для до-ставки борсодержащих препаратов для НÇТ [41,42]. Данные по выживаемости крыс с перевивной глиомой F98 могут обеспечить основу для I фазы клинических испытаний по оценке безопасности и потенциальной терапевтической ýффективно-сти CED-доставки карбоплатина у пациентов с рецидивирующей глиобластомой, а в дальнейшем и проведение II фазы клинических испытаний по Обзоры и лекции применению карбоплатина в комбинации с ради-ационной терапией [33,34].…”

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part II: Arborizing Catheter for Convection-Enhanced Delivery in Tissue Phantoms

“…With these initial studies, CED was established as a viable method for providing regional distribution of large molecules, such as proteins and some conventional chemotherapeutic agents, in the brain (6)(7)(8)(9). Compared with other therapies, CED minimizes systemic and CNS toxicity by local delivery of high concentrations of therapeutics directly to the brain tissue and has led to treatment applications in several cerebral disorders, including Parkinson' s (10,11), epilepsy (12), Alzheimer' s (13,14), and malignant gliomas (4,5,(15)(16)(17)(18)(19)(20)(21).…”