Radiotherapy followed by adjuvant temozolomide with or without neoadjuvant ACNU-CDDP chemotherapy in newly diagnosed glioblastomas: a prospective randomized controlled multicenter phase III trial

Kim, Il Han; Park, Chul‐Kee; Heo, Dae Seog; Kim, Chae-Yong; Rhee, Chang Hun; Nam, Do Hyun; Lee, Jun Young; Han, Jung Ho; Lee, Se‐Hoon; Kim, Tae Min; Kim, Dong-Wan; Kim, Jeong Eun; Paek, Sun Ha; Kim, Dong-Gyu; Kim, In Ah; Kim, Yu Jung; Kim, Jee Hyun; Park, Byung Joo

doi:10.1007/s11060-010-0427-y

Cited by 32 publications

(20 citation statements)

References 17 publications

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“…18 Aggressive treatments using radiotherapy followed by adjuvant TMZ with chemotherapeutic agents previously showed the best OS (28 months). 9 However, in that study, the enrollment was stopped due to an unacceptable frequency of toxicity related to the neoadjuvant chemotherapeutic agents. Clinical use of 6 weeks of continuous TMZ often causes Grade 3 or 4 lymphopenia, 7,11 and this was seen in the present study.…”

Section: Discussionmentioning

confidence: 99%

Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma

Ishikawa

Muragakı

Yamamoto

et al. 2014

JNS

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Object Temozolomide (TMZ) may enhance antitumor immunity in patients with glioblastoma multiforme (GBM). In this paper the authors report on a prospective Phase I/IIa clinical trial of fractionated radiotherapy (FRT) concomitant with TMZ therapy, followed by treatment with autologous formalin-fixed tumor vaccine (AFTV) and TMZ maintenance in patients with newly diagnosed GBM. Methods Twenty-four patients (age 16–75 years, Karnofsky Performance Scale score ≥ 60% before initiation of FRT) with newly diagnosed GBM received a total dose of 60 Gy of FRT with daily concurrent TMZ. After a 4-week interval, the patients received 3 AFTV injections and the first course of TMZ maintenance chemotherapy for 5 days, followed by multiple courses of TMZ for 5 days in each 28-day cycle. Results This treatment regimen was well tolerated by all patients. The percentage of patients with progression-free survival (PFS) ≥ 24 months was 33%. The median PFS, median overall survival (OS), and the actuarial 2- and 3-year survival rates of the 24 patients were 8.2 months, 22.2 months, 47%, and 38%, respectively. The median PFS in patients with a delayed-type hypersensitivity (DTH) response after the third AFTV injection (DTH-2) of 10 mm or larger surpassed the median length of follow-up for progression-free patients (29.5 months), which was significantly greater than the median PFS in patients with a smaller DTH-2 response. Conclusions The treatment regimen was well tolerated and resulted in favorable PFS and OS for newly diagnosed GBM patients. Clinical trial registration no.: UMIN000001426 (UMIN clinical trials registry, Japan).

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Section: Discussionmentioning

confidence: 99%

Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma

Ishikawa

Muragakı

Yamamoto

et al. 2014

JNS

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“…It has also been used as an adjuvant in the treatment of pediatric brain tumors [4]. However, adult GBM patients treated with CDDP suffer severe kidney and neurotoxicity, even at sub-therapeutic drug concentrations [5–7]. Methods that reduce off-target toxicity and/or increase local delivery to permit a decrease in systemic dose would greatly increase CDDP’s utility in the treatment of brain tumors [5].…”

Section: Introductionmentioning

confidence: 99%

MR image-guided delivery of cisplatin-loaded brain-penetrating nanoparticles to invasive glioma with focused ultrasound

Timbie

Afzal

Date

et al. 2017

Journal of Controlled Release

105

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Systemically administered chemotherapeutic drugs are often ineffective in the treatment of invasive brain tumors due to poor therapeutic index. Within gliomas, despite the presence of heterogeneously leaky microvessels, dense extracellular matrix and high interstitial pressure generate a “blood-tumor barrier” (BTB), which inhibits drug delivery and distribution. Meanwhile, beyond the contrast MRI-enhancing edge of the tumor, invasive cancer cells are protected by the intact blood-brain barrier (BBB). Here, we tested whether brain-penetrating nanoparticles (BPN) that possess dense surface coatings of polyethylene glycol (PEG) and are loaded with cisplatin (CDDP) could be delivered across both the blood-tumor and blood-brain barriers with MR image-guided focused ultrasound (MRgFUS), and whether this treatment could control glioma growth and invasiveness. To this end, we first established that MRgFUS is capable of significantly enhancing the delivery of ~60 nm fluorescent tracer BPN across the blood-tumor barrier in both the 9L (6-fold improvement) gliosarcoma and invasive F98 (28-fold improvement) glioma models. Importantly, BPN delivery across the intact BBB, just beyond the tumor edge, was also markedly increased in both tumor models. We then showed that a CDDP loaded BPN formulation (CDDP-BPN), composed of a blend of polyaspartic acid (PAA) and heavily PEGylated polyaspartic acid (PAA-PEG), was highly stable, provided extended drug release, and was effective against F98 cells in vitro. These CDDP-BPN were delivered from the systemic circulation into orthotopic F98 gliomas using MRgFUS, where they elicited a significant reduction in tumor invasiveness and growth, as well as improved animal survival. We conclude that this therapy may offer a powerful new approach for the treatment invasive gliomas, particularly for preventing and controlling recurrence.

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“…Another study conducted by Kim et al [20] has identified the superiority of introducing both ACNU and CDDP into TMZ compared with single TMZ. Although TMZ, ACNU and CDDP were classified as alkylating agents, they had different mechanisms to control tumour cells.…”

Section: Discussionmentioning

confidence: 99%

A network meta-analysis: the overall and progression-free survival of glioma patients treated by different chemotherapeutic interventions combined with radiation therapy (RT)

Ding

Wang

et al. 2016

Oncotarget

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Different chemotherapy drugs are generally introduced in clinical practices combining with therapy for glioma treatment. However, these chemotherapy drugs have rarely been compared with each other and the optimum drug still remains to be proved. In this research, medical databases were consulted, PubMed, Embase and Cochrane Library included. As primary outcomes, hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) with their corresponding 95% credential intervals (CrI) were reported. A network meta-analysis was conducted; the surface under the cumulative ranking curve (SUCRA) was utilized for treatment rank and a cluster analysis based on SUCRA values was performed. This research includes 14 trials with 3,681 subjects and eight interventions. In terms of network meta-analysis, placebo was proved to be inferior to the combination of temozolomide (TMZ), nimustine (ACNU) and cisplatin (CDDP). Also, bevacizumab (BEV) in conjunction with TMZ were significantly more effective than placebo with an HR of 0.40. The estimated probabilities from SUCRA verified the above outcomes, confirming that the combination of TMZ, ACNU and CDDP exhibited the highest ranking probability of 0.889 with respect to OS, while BEV in combination with TMZ - with a probability of 0.772 - ranked the first place with respect to PFS. According to the results of this network meta-analysis, the combination of (1) TMZ, ACNU and CDDP; (2) BEV in combination with TMZ and (3) cilengitide in combination with TMZ, are considered as the preferable choices of chemotherapy drugs for glioma treatment.

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Radiotherapy followed by adjuvant temozolomide with or without neoadjuvant ACNU-CDDP chemotherapy in newly diagnosed glioblastomas: a prospective randomized controlled multicenter phase III trial

Cited by 32 publications

References 17 publications

Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma

Phase I/IIa trial of fractionated radiotherapy, temozolomide, and autologous formalin-fixed tumor vaccine for newly diagnosed glioblastoma

MR image-guided delivery of cisplatin-loaded brain-penetrating nanoparticles to invasive glioma with focused ultrasound

A network meta-analysis: the overall and progression-free survival of glioma patients treated by different chemotherapeutic interventions combined with radiation therapy (RT)

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