Patterns of Progression in Pediatric Patients with High-Grade Glioma or Diffuse Intrinsic Pontine Glioma treated with Bevacizumab-Based Therapy at Diagnosis

The first hints of data from a Cincinnati/Lurie Children's study using temozolomide, irinotecan and avastin appears to be coming out with a poster presentation at the 3rd biennial Pediatric Basic and Translational Research Conference looking at patterns of progression with an avastin-based therapy for kids with newly diagnosed DIPG or high grade glioma.

The issues of potential increased invasiveness and spread have been popping up for the past few years. We have seen discussions of this in internet-based communities as well as publications in adult GBM patients.   Common terms related to this are "diffuse invasiveness" and "evasive resistance".   The adult literature has some that do not believe that avastin increases remote relapses.  There is very little regarding children relapse patterns with bevacizumab-based therapies.

In this study of 17 patients (14 DIPG and 3 HGG), 12 patients had progressive disease in a median time of 8.2 months.  In nine patients the furst progression was local and  in the remaining three the progression was local, diffuse and distant.   However with further progressive disease a total of six children had diffuse or distant progression.

The authors speculate that these findings might be explained by increasing invasiveness through co-opting native blood vessels or activation of other pro-angiogenic pathways.     

It would be interesting to have direct comparison to non-bevacizamab-based therapies for comparison as other authors have indicated a high risk of leptomeningeal dissemination with DIPG.  Interestingly, in that study 8 of the 16 children had leptomeningeal spread but only the 3 with anti-VEGF (2 with avastin and 1 with vandetanib) had spread to bilateral cerebral hemispheres.  The other 5 had spread to the spinal cord or posterior fossa.

It is likely questions like this is where a registry can be valuable if one is able to look at a large number of imaging studies. 

Reference:
Patterns of Progression in Pediatric Patients with High-Grade Glioma or Diffuse Intrinsic Pontine Glioma treated with Bevacizumab-Based Therapy at Diagnosis
https://soc-neuro-onc.conference-services.net/reports/template/onetextabstract.xml?xsl=template/onetextabstract.xsl&conferenceID=3467&abstractID=736163

A Study of Bevacizumab Therapy in Patients With Newly Diagnosed High-Grade Gliomas and Diffuse Intrinsic Pontine Gliomas
http://clinicaltrials.gov/ct2/show/NCT00890786?term=dipg&rank=10

Bevacizumab does not increase remote relapse in malignant glioma
http://www.ncbi.nlm.nih.gov/pubmed/21446027

Prospective neuroaxis surveillance reviews a high risk of leptmeningeal dissemination in diffuse intrinsic pontine glioma.
http://www.ncbi.nlm.nih.gov/pubmed/20623246

New Trial Pending: Reirradiation for DIPG

Every once in awhile I will just randomly go through clinicaltrials.gov searching to see if anything new has been put up.   I had gone through a few times recently seeing two reirradiation trials listed- one open and one not yet open.   Knowing of the MD Anderson trial I thought it was just a computer glitch.   When I finally opened the page, it was a surprise it wasn't MDA but a trial based in Israel.  

It not that Israel hasn't come up before in the brain tumor community.   It definitely has.  There has been interest in the Newcastle Disease oncolytic virus and the Novocure device on internet groups to which I belong.   However, both have had issues that made it problematic in the DIPG community.   In the former lack of a tissue diagnosis could be a hurdle and the latter has significant issues with pad placement for electrical fields have made the device not possible- at least not yet.   It is just that Israel isn't one of the places that is often mentioned in DIPG work.

It would certainly seem that this pending trial was based on the MD Anderson work published last year (abstract link below).   In that pilot project 4 of 6 children had significant clinical improvement after  receiving re-irradiation at symptom progression.   Three of these children were able to walk again after re-irradiation.   The mean progression free survival was 5 months.  Those children with the longest time interval between radiation courses had the greatest benefit.

This trial is interesting it is allowing for a short interval for radiation at a minimum of 4 months.  Since at one time it was thought that re-irradiation wasn't even possible is is a huge shift in thinking.  

Another interesting thing is the increased specifics on the inclusion criteria-
-diagnosis of DIPG based on short classic history,
-clinical signs (long tract signs, cranial nerve deficits and ataxia), and
-classic MRI features (more than 2/3 of the tumor is located within the pons and tumor encompasses more than 60% of the pons).

I think we are going to increasingly see this type of specific DIPG definition be articulated in trial inclusion criteria.   It is important to be able to better interpret results.

The increasing international inertia to fight DIPG is palpable.  It is good to see another country join in the fight to try to do something to help these children.

Reference:
Israel- Hadassah Medical Organization
Palliative Re-irradiation for Progressive Diffuse Intrinsic Pontine Glioma (DIPG) in Children
http://clinicaltrials.gov/ct2/show/NCT01777633?term=dipg&rank=3

MD Anderson
Diffuse Intrinsic Pontine Glioma (DIPG) Reirradiation (ReRT)
http://clinicaltrials.gov/ct2/show/NCT01469247?term=dipg&rank=13

Palliative reirradiation for progressive diffuse intrinsic pontine glioma.
Am J Clin Oncol. 2012 Feb;35(1):51-7. 
http://www.ncbi.nlm.nih.gov/pubmed/21297433