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."

Reference:
Robotic-guided convection-enhanced delivery of carboplatin for advanced brainstem glioma
Acta Neurochir (Wien). 2013 Apr 18. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/23595829

Netherlands Radiolabeled Bevacizumab Trial

In the age of molecularly-targeted chemotherapy, diffuse intrinsic pontine gliomas are tough tumors.  DIPGs seem to be molecularly heterogenous tumors- not only between individuals but also within a single tumor.  If one can not obtain tissue then it is impossible to know if a particular tumor even has the target.  And if one does get a biopsy the concern is is really representative?

There is also the concern perhaps the brainstem is more difficult to get agents in- is the blood brain barrier just more tight in that area?

For me the question has been, how do we address these concerns clinically?  It appear that the researchers at VU University Medical Center in the Netherlands are trying to look at these questions by using an immuno-PET approach.

Immuno-PET scanning  uses a radio-labeled monoclonoal antibody.   The idea is that the radio-labeled agent will stick at the place where there is the specific receptor and the tag will let it light up on the scan.   One could think of it as "a comprehensive immunohistochemical stain in vivo".    In this case the monoclonal antibody bevacizumab is labeled with 89Zr.  PET scans will be done at 1, 72 and 144 hours after administration.

Immuno-PET looks like a  novel way to get answers to some of these questions.  My hope is that this study will provide new knowledge on drug distribution with a anti-VEGF in DIPG.   Since pediatric high grade gliomas are also included it will be interesting to compare these two different populations.

This research has been supported by Stichting Semmy.

Reference:
Determining the tumor uptake of labelled bevacizumab in children with high grade or diffuse intrinsic pontine glioma on PET Scans
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3518

Immuno-PET: a navigator in monoclonal antibody development and applications.
Full Text-http://theoncologist.alphamedpress.org/content/12/12/1379.long

Is Biopsy Safe in DIPG? An Institutional Experience

This spring abstract season which means one can comb through the abstracts to find the newest research being presented- sometimes more than a year before publication.   The hope in finding and highlighting relevant meeting abstracts is to significantly shorten that time period in figuring out who is doing what.  

On of the meetings with potential is the 26th Annual American Society of Pediatric Hematology and Oncology (ASPHO) Anual  Meeting being held in Miami from April 24-27.   With all the different pediatric blood and cancer disorders, I don't usually expect much success in looking for brain tumor abstracts let alone DIPG.   This year, though,  I was surprised by abstract 750 (page S67):

Is Biopsy Safe in Diffuse Intrinsic Pontine Glioma?

An Institutional Experience

The surprise didn't end there.   Although the institutions is one of the collaborators for the multi-institutional trial with molecular determination for treatment by upfront biopsy,  it is not one that has been obviously on the forefront of the US biopsy debate- Children's Hospital of Michigan in Detroit.  

These authors report on 22 newly diagnosed children with DIPG between 2002 and 2012.    Stealth guided biopsies were performed in 68% of the cases.   There were no deaths related to biopsy.  Three of the fifteen children undergoing biopsy has transient issues post-operative which resolved within two weeks.   The issues included one child developed a facial nerve palsy, one child has some speech difficulty and extremity weakness and the third has ataxia and swallowing difficulties.

All biopsies showed gliomas (grade 2-4). 

The authors conclude that biopsy at their institution has been relatively safe and the resulting tissue will allow for molecular profiling which may lead to targeted therapy and perhaps in the future prolonged survival or a cure.

So, why is the percentage of biopsy so high at this institution?   These authors report a case of theirs in which a child was found to have a PNET tumor rather than a glioma.   Subsequently, biopsy is considered in the majority of these tumors at diagnosis.

Reference:
Molecularly Determined Treatment of Diffuse Intrinsic Pontine Glioma
http://clinicaltrials.gov/ct2/show/NCT01182350?term=dipg&rank=5

DIPG Yahoogroup 5th Anniversary

Today marks the 5th anniversary of the DIPG Yahoogroup.  Started by on April 16th, 2008 by one mother who wanted to have a place for DIPG parents to talk with one another and share experiences as well as information.   From that one, there are now 616 members listed with almost 25,000 posts.

So much has changed in those five years.   Back in 2008,  it was common to hear parents say brainstem glioma not realizing how heterogeneous that term really was.   I don't remember any listings of trials on clinicaltrials.gov under DIPG.   Today there are 26 listed making it much easier for parents to locate and sort through these trials.   And back there research was severely limited because there was no tissue to examine; and because of the lack of tissue there were no cell lines or representative animal models.

The research landscape was just beginning to change for DIPG with the French biopsy study having just been published the year before and several institutions working to gather post-mortem samples.  The start of the list coincided with the rapid expansion of DIPG research.

I firmly believe it is because of some of the members of this group that DIPG research was pushed more quickly. Some played their part on spreading the word on tumor donation while others funded workshops, trials and research.   Often interesting items appeared on the list significantly before publication like the MD Anderson reirradation pilot- perhaps pushing the spread of information faster than ever has been seen before.

Here is a listing of some of the important events in DIPG over the past decade:

2002- Sick Kids start autopsy collection of DIPGs
2005- France starts trial with upfront biospy
2006- St Jude stars autopsy collection of DIPGs
2007- France first reports on trial with upfront biopsy
2008- DIPG Yahoogroup opened
2009- First International DIPG Meeting in Barcelona
2009- FDA DIPG biopsy hearing
2009- Dylan donates tumor to Stanford
2009- First CED trial on recurrent DIPG open in US
2010- Toronto DIPG Think Tank
2010- First DIPG Genetic Analysis Publication
2011- Amsterdam DIPG meeting
2011- Stanford reveals first DIPG neurosphere
2011- Vaccine study for newly diagnosed DIPG begins at Stanford
2011- First DIPG/Oncolytic Virus Case
2011- DIPG.org Symposium
2011- DIPG Preclical Consortium formed
2011- DIPG Registry
2011- MD Anderson opens first DIPG Reiiradiation trial
2011- DIPG Concensus Conference at the NIH
2012- DIPG Barcelona Conference
2012- ACCO Book- Understanding the Journey
2012- DIPG Genomics Repository
2012- US multi-institution biopsy trial begins
2012- CED trial for newly diagnosed DIPG opens at Cornell
2013- Academic Colloquium: State of the Art in DIPG (Amsterdam)

I extend deep gratitude to all that participated in the list which has helped get us to where we are today.