Radiation therapy combined with intracerebral administration of carboplatin for the treatment of brain tumors

Abstract

BackgroundIn this study we determined if treatment combining radiation therapy (RT) with intracerebral (i.c.) administration of carboplatin to F98 glioma bearing rats could improve survival over that previously reported by us with a 15 Gy dose (5 Gy × 3) of 6 MV photons.MethodsFirst, in order to reduce tumor interstitial pressure, a biodistribution study was carried out to determine if pretreatment with dexamethasone alone or in combination with mannitol and furosemide (DMF) would increase carboplatin uptake following convection enhanced delivery (CED). Next, therapy studies were carried out in rats that had received carboplatin either by CED over 30 min (20 μg) or by Alzet pumps over 7 d (84 μg), followed by RT using a LINAC to deliver either 20 Gy (5 Gy × 4) or 15 Gy (7.5 Gy × 2) dose at 6 or 24 hrs after drug administration. Finally, a study was carried out to determine if efficacy could be improved by decreasing the time interval between drug administration and RT.ResultsTumor carboplatin values for D and DMF-treated rats were 9.4 ±4.4 and 12.4 ±3.2 μg/g, respectively, which were not significantly different (P = 0.14). The best survival data were obtained by combining pump delivery with 5 Gy × 4 of X-irradiation with a mean survival time (MST) of 107.7 d and a 43% cure rate vs. 83.6 d with CED vs. 30-35 d for RT alone and 24.6 d for untreated controls. Treatment-related mortality was observed when RT was initiated 6 h after CED of carboplatin and RT was started 7 d after tumor implantation. Dividing carboplatin into two 10 μg doses and RT into two 7.5 Gy fractions, administered 24 hrs later, yielded survival data (MST 82.1 d with a 25% cure rate) equivalent to that previously reported with 5 Gy × 3 and 20 μg of carboplatin.ConclusionsAlthough the best survival data were obtained by pump delivery, CED was highly effective in combination with 20 Gy, or as previously reported, 15 Gy, and the latter would be preferable since it would produce less late tissue effects.

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

“…Our median survival times of rats treated with carboplatin were generally shorter than those reported by the teams of Elleaume and Barth. For example, MeST of 45 days and 43 days were obtained respectively by Rousseau J. et al [13] and Yang W. et al [20], while only 38.5 days was observed in our study when treated with carboplatin. The differences may be due to the following reasons.…”

“…Additionally, a phase I clinical trial showed that it was safe and feasible to deliver carboplatin by CED to treat glioblastoma [18]. However, due to the large diversity of the techniques, animal models, and/or drug dosages used in different studies [12,13,19,20], it is unclear if the CED of one particular platinum-based antineoplastic agent is better than the others. Moreover, it is paramount to evaluate the liposomal formulations of platinum drugs and compare their performance to that of free platinum drugs, particularly since it has been reported that liposomal chemotherapy drugs delivered by CED have longer retention times in the tumor area, and can further extend survival [21].…”

Novel delivery methods bypassing the blood-brain and blood-tumor barriers

“…114 This method was pioneered by Neuwelt and colleagues in 1979, 119 and the effectiveness of a 25% mannitol solution was investigated in clinical trials in 1981. 120 Further analysis in rat models indicated that this disruption of the BBB is maintained for approximately 30 minutes 82,179 and that permeability is achieved for between 15 minutes and 4 hours, depending on the molecular weight of the agent used. Current in vivo research efforts involve intraarterial injection of the hyperosmotic agent that induces BBB disruption and subsequent intraarterial injection of the drug of interest.…”

Blood—brain barrier permeability in healthy rats and rats with experimental C6 glioma after fractionated radiotherapy of the brain

“…В последнее время появляются данные о положи-тельном результате при предварительном облуче-нии головного мозга с опухолями перед химиотера-пией, однако диапазон применяемых доз фракцио-нированной радиотерапии довольно широк [4][5][6]. К примеру, большинство исследователей [7][8][9] счи-тают, что лучевая терапия в дозах от 20 до 30 Гр с размером фракции 2 Гр может применяться для прорыва ГЭБ без особых побочных эффектов.…”