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Friday, April 19, 2013

UK Gives CED a Go

Just yesterday a DIPG/CED article came out electronically ahead of print in the journal Acta Neurochirugica-essentially a case report of a 5 year-old-boy with progressive DIPG who received carboplatin by CED- in Bristol, UK!

Since drug delivery into the pons has been considered a major hurdle in the treatment of pediatric DIPG,  there has been increasing world-wide interest in convection-enhanced delivery as a novel treatment for DIPG.  In the US there is the Cornell trial using 124I-8H9, the NIH trial using IL13-PE38QQR and a recent publication out of Columbia using topetecan.   Although not specifically termed a DIPG, Japanese physicians reported in 2011 about the use of nimustine via CED for a pediatric infiltrating brainstem GBM with improvement of symptoms and regression of the lesion. Basic science research has been going on in Spain using CED to deliver oncolytic viruses into DIPG lesions.   The Netherlands seems to be doing basic science CED research using carmustine.

It appears that the UK was on the forefront of the biopsy debate by offering families participation in the early French biopsy study.   Dr. Darren Hargrave reported on this back in 2009 at the first International DIPG conference in Spain.   One can view the lecture (go to 19:30 to start on the UK biopsy involvement).  One the CED front, however, the UK is not a country that has really come up before in the literature or internet.   Thus, this case report was somewhat surprising.

In this technical notes publication,  the authors report the "first use of carboplatin for the treatment of advanced DIPG using a robot-guided catheter implantation technique" performed on a 5 year old boy with progressive DIPG.  The child sounds like he had a typical DIPG course developing ataxia, double vision and swallowing issues over a month.    The initial MRI showed expansive pontine mass extending into the midbrain and right cerebellar peduncle.  He was first treated with radiation and steroids.   Because of progressive deterioration, the child underwent CED therapy nine months after diagnosis.

As this is a technical notes article, the publication goes into detail on the method of CED infusion (and has several MRI images).    Here is a very basic description of the procedure and infusion.   A catheter is placed through a typical transfrontal approach (3cm frontal skin incision).  After fixation the child underwent MR imaging to for drug distribution investigation.   Once this was determined the child recovered from anesthesia and the carboplatin infusion continued.  Initial carboplatin infusion occurred over three consecutive days.   Then there was a 4-day rest period followed by another 2 days of infusion.  The catheter was replaced with a stylet on day 12 to remain as a guide tube if needed for further infusions.  Discharge occurred on day 14 after the procedure.

During infusion, the child had some worsening neurological symptoms; however, a month after infusion he was more alert, was able to decrease his steroid use by more than half but his neurological status was mixed with some things were improved and others were worse.  Two months after infusion the boy had a rapid deterioration and died.

The discussion highlights a number of "technical challenges" with CED especially revolving around getting sufficient drug concentration with in the tumor which include reflux of the infusing drug and poor drug distribution.   Also "off target" side effects have been barriers.   To me these off-target side effects are not unexpected as one is infusing a liquid under pressure into a relative small tight space.  

The authors felt that this case demonstrated the feasibility and safety of CED infusion for pediatric DIPG.   Most importantly they end with something to watch for in the future...." It is our intention to use the experience gained in this case to develop a robust protocol for a phase 1 clinical trial of convection-enhanced delivery of carboplatin for progressive brainstem glioma."

Robotic-guided convection-enhanced delivery of carboplatin for advanced brainstem glioma
 2013 Apr 18. [Epub ahead of print]

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