Skip to main page content
U.S. flag
See More

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Mar 26;2(1):vdaa033.
doi: 10.1093/noajnl/vdaa033. eCollection 2020 Jan-Dec.

Phase I trial of convection-enhanced delivery of nimustine hydrochloride (ACNU) for brainstem recurrent glioma

Ryuta Saito  1 , Masayuki Kanamori  1 , Yukihiko Sonoda  1 , Yoji Yamashita  1 , Kenichi Nagamatsu  1 , Takaki Murata  2 , Shunji Mugikura  2 , Toshihiro Kumabe  1 , Eva Wembacher-Schröder  3 , Rowena Thomson  3 , Teiji Tominaga  1
Affiliations

Phase I trial of convection-enhanced delivery of nimustine hydrochloride (ACNU) for brainstem recurrent glioma

Ryuta Saito et al. Neurooncol Adv. .

Abstract

Background: Treatment options for patients suffering brainstem gliomas are quite limited as surgery is not an option against intrinsic tumors at brainstem and chemotherapy generally failed to demonstrate its efficacy. Intracerebral convection-enhanced delivery (CED) is a novel approach for administering chemotherapy to patients with brain tumors. We present the results of phase I trial of CED of nimustine hydrochloride (ACNU), designed to determine the maximum tolerable concentration of ACNU, for patients with recurrent brainstem gliomas.

Methods: Sixteen patients, aged 3-81 years old, suffering from recurrent brainstem gliomas, including diffuse intrinsic pontine glioma patients as well as patients with recurrent gliomas that originated from non-brainstem sites, were enrolled in this trial between February 2011 and April 2016. The dose/concentration escalation trial included 3 dose/concentration groups (0.25, 0.5, and 0.75 mg/mL, all at 7 mL) to determine the safety and tolerability of CED of ACNU. Real-time monitoring of drug distribution was performed by mixing gadolinium-tetraazacyclododecanetetraacetic acid (Gd-DOTA) in the infusion solution. CED of ACNU was given in combination with oral or intravenous temozolomide chemotherapy.

Results: CED of ACNU demonstrated antitumor activity, as assessed by radiographic changes and prolonged overall survival. The recommended dosage was 0.75 mg/mL. Drug-associated toxicity was minimal.

Conclusions: Intracerebral CED of ACNU under real-time monitoring of drug distribution, in combination with systemic temozolomide, was well tolerated among patients with recurrent brainstem gliomas. The safety and efficacy observed suggest the clinical benefits of this strategy against this devastating disease. Based on this phase I study, further clinical development of ACNU is warranted.

Keywords: brainstem; convection-enhanced delivery; nimustine hydrochloride; recurrent glioma; temozolomide.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
CED infusion in a representative patient. (A) Pre-infusion contrast-enhanced T1-weighted sagittal image. (B) Image showing the complex anatomy. Automatic object creation and fiber tracking can help define the clinical target volume, locate and avoid critical structures during surgical planning, and find the optimal trajectory. Yellow, tumor; purple, ventricle; blue-dotted line, planned catheter tract. (C) Automatic sulcus delineation overlaid on the anatomical images and geometrical visualization of the recommended distance from the catheter tip to avoid structures at risk and minimize the risk of leakage into CSF space. (D) Local detection of fiber bundles in the region of interest provides information about potential leakage pathways, thereby helping to identify an optimal trajectory. (E) Retrospective analysis of catheter placement accuracy. Planned trajectory (red) versus the actual catheter position (blue). Distribution of tracer agent (yellow outline). (F) The volume of distribution at each MRI time point plotted against the volume of infusion. Vd/Vi was almost 2 at the beginning of infusion, but gradually slowed with Vd plateauing at 6–7 mL.
Figure 2.
Figure 2.
Waterfall plot of the maximum percentage change from baseline in the tumor volume of target lesions (N = 14). White boxes, patients received 0.25 mg/mL infusion; gray boxes, patients received 0.5 mg/mL infusion; black boxes, patients received 0.75 mg/mL infusion. Responses were categorized according to that of Response Assessment in Neuro-Oncology criteria.
Figure 3.
Figure 3.
A case of a 32-year-old female treated for DIPG for 4 months prior to starting CED of ACNU. She was treated with local 54 Gy irradiation and then followed up at another hospital for her initial disease (A and G: 3 months before CED). She was referred to us 1 month prior to the CED of ACNU (B and H). Treatment was given against a rapidly enhancing mass (C). After treatment, TMZ monotherapy was continued (D and I) 2 months after CED (E and J: 5 months after CED). Her symptoms of truncal ataxia, diplopia, and dysarthria gradually recovered. Imaging revealed complete remission of the tumor at 7 months after the CED of ACNU (F and K). (A–F) T1-weighted images with contrast enhancement and (G–K) T2-weighted images.
Figure 4.
Figure 4.
A case of a 3-year-old female treated for DIPG for 6 months prior to starting CED of ACNU (A and F). She was treated with local 54 Gy irradiation plus concomitant TMZ and followed up at another hospital. Due to growing contrast enhancement, she was referred to us and underwent CED of ACNU (B and G). After treatment, TMZ monotherapy was continued. Her symptoms of truncal ataxia, diplopia, and right hemiparesis gradually improved. Images reveal the responses until 3 months after CED of ACNU (C and H: 1 month after CED; D and I: 2 months after CED; E and J: 3 months after CED). (A–E) T1-weighted MRI with contrast enhancement and (F–J) T2-weighted images.
See this image and copyright information in PMC

References

    1. Stiller CA, Nectoux J. International incidence of childhood brain and spinal tumours. Int J Epidemiol. 1994;23(3):458–464. - PubMed
    1. Hargrave D, Bartels U, Bouffet E. Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol. 2006;7(3):241–248. - PubMed
    1. Vanan MI, Eisenstat DD. DIPG in children—what can we learn from the past? Front Oncol. 2015;5:237. - PMC - PubMed
    1. Hu J, Western S, Kesari S. Brainstem glioma in adults. Front Oncol. 2016;6:180. - PMC - PubMed
    1. Groothuis DR. The blood-brain and blood-tumor barriers: a review of strategies for increasing drug delivery. Neuro Oncol. 2000;2(1):45–59. - PMC - PubMed

LinkOut - more resources