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

Dana Farber DIPG Research Receives a Half Million Dollars

Mikey loved baseball and the New York Yankees, the Doobie Brothers and his dog named Cody.   On Mikey's 11th birthday, January 6, 2008, life as this family knew it ceased to exist.   They first heard the letters- DIPG.  After radiation and a radiosensitizer trial ( Motexafin Gadolinium), his tumor shrank about 85% by April; but byAugust, he started to have right sided numbness, problems walking and difficulty swallowing.     Mikey Czech died on September 7, 2008.

In Mikey's memory, the Stephen J Czech family founded the Mikey Czech foundation with a mission  to establish a leading neuro-oncology translational research laboratory, raise awareness of DIPG, fund research and cure pediatric brain tumors.

In their search to find research trying to cure DIPG, they found a physician, Mark Kieran MD, PhD, completely frustrated at the lack of prognostic change for DIPG in 30 years and a desire to try a new approach.   Biopsies were essentially stopped in the early 1990s before it was even possible to study tumor molecular biology and now seemed to be the right time to take advantage of all the knowledge gained in neurosurgical technique, cancer pharmacology and tumor molecular biology to try to make a difference for DIPG kids.

Dogma doesn't change easily.  For year, Dr Kieran challenged his colleagues on this front.   Little by little others came to the same perspective.  In December 2012, a multi-institutional clinical trial with molecularly determined treatment for the newly diagnosed child with DIPG commenced at Boston Children's.   Today, five other institutions (Lurie Children's in Chicago, Johns Hopkins,  Seattle Children's, Cook Children's in Texas and Washington University in St Louis) also have this trial open.
Watch Dr Kieran discuss a one minute presentation on DIPG research  (open in a different window)

This trial faced other difficulties as well- in particular, funding.   This trial is using already known drugs  so isn't a trial that would be funded by a pharmaceutical company.   It was up to private funding to make this happen.   Mikey Czech Foundation has been a big part of this- and with the donation of a half million dollars today continues to be a sustained supporter of Dana Farber's leading edge work.

One should note that the Boston researchers have not been sitting around waiting for the trial to start.   Biospies have been happening for years in France.  With the financial backing of these foundations,  the researchers in France and Boston collaborated to look at 20 newly diagnosed DIPG specimens- before they could be changed by radiation and chemotherapy.  Here is a link to the abstract published last year.

In this fight we will take Mikey's motto:

"Never, Never, Never Give Up!"

Note- I am aware of several organizations that have come together to fund this innovative research- The Zach Carson DIPG Fund, the Ellie Kavalieros DIPG Fund, The Prayers From Maria Foundation, Children's Hospital of Los Angeles Imaging Center, The Pediatric Brain TUmor Research and Clinical Fund at Dana-Farber Cancer Institute,Stop and Shop Pediatric Brain Tumor Research Fund and Hope for Caroline

References:
The Mikey Czech Foundaiton Contributes $500,000 to DIPG Research at Dana-Farber Cancer Institute-Harvard Medical School (2013)
http://finance.yahoo.com/news/mikey-czech-foundation-contributes-500-121400450.html

The Mikey Czech Foundation Funds New Hope for Cancer Research (2012)
http://thecristianriverafoundation.blogspot.com/2012/01/mikey-czech-foundation-funds-new-hope.html

Molecularly Determined Treatment of Diffuse Intrinsic Pontine Gliomas (DIPG)
http://clinicaltrials.gov/show/NCT01182350

Mikey Czech Foundation
http://www.mikeyczech.org/

Focus On Researh- Xiao Nan Li

Dedicated to a special boy,  Paul Alexander Coleman III, who is continuing to make an impact.....

Because of the trifecta of basic science hurdles- no tissue, no cell lines, no animal models- DIPG bench research has only recently begun.  This has only been possible because of the efforts of a few individuals struggling to make the previously impossible possible- make animal models from an inoperable tumor.  One of these pioneers- Xiao Nan Li MD, PhD (Baylor College of Medicine/Texas Children's Cancer Center).

Dr Li's interest is in the fields of cancer stem cells, experimental therapeutics and diagnostic markers with a particular focus on developing "clinically relevant animal models" for preclinical testing.

I first became aware of Dr Li when a fellow brain tumor parent sent her son's post-mortem specimen across the from the east coast to Texas to try to make a difference for medulloblastoma.  The lab wasn't only interested in medulloblastoma.   Dr Li has established more than 25 xenograft mouse models of several different pediatric brain tumors.  At some time,  a post mortem DIPG specimen was obtained and through the lab's work a door was unlocked for DIPG.  Dr Li was able to establish a DIPG animal mouse model from this tissue and the scientific value of DIPG autopsy specimens skyrocketed.

Although the lab is interested in fighting all pediatric brain tumors there seems to have been a special focus on DIPG.   Texas Children's has cell lines and thus became one of the initial members of the DIPG Pre-clincal consortium which is collaboratively working on rapid analysis of the cell lines and drug testing.

The lab has at least 5 different DIPG mouse xenografts that can be used for other types of research.  One of these research endeavors is using oncolytic viruses in the DIPG mice he developed.  Dr Xaio Nan Li will be presenting his work in a mouse model on eliminating therapy resistant DIPGs with an oncolytic virus at the DIPG Symposium in Cincinnati on May 3rd.   A link to the grant executive summary funded by the Cure Starts Now is listed below.

This oncolytic virus research is exciting especially in light of the recent publication out of University of Alabama looking at this issue in pediatric gliomas.   Although the publication is a different virus, the idea is essentially the same.  Novel therapies are going to be needed to eliminate treatment resistent subpopulations while sparing normal tissue.  Oncolytic virus have been one of the innovative treatment that might be a weapon in the future against DIPG as well as other gliomas and brain tumors.

References:
Neuro-Oncology Research Lab of Dr Xiao Nan Li
http://ccitonline.org/tccc_production_old/cancer-genomics-li/

Harnessing Autopsied DIPG Tumor Tissues for Orthotopic Xenograft Model Development in the Brain Stems of SCID mice- Grant Award Final Report
http://www.dtic.mil/cgi-bin/GetTRDoc?AD=ADA568355

Eliminating Therapy-Resistant Diffuse Intrinsic Pontine Gliomas with Oncolytic Picorna Virus SVV-001: an in vivo Study in Intra-brain Stem Xenograft Mouse Models- Grant Executive Summary
http://www.thecurestartsnow.org/_pdfs/grant_2011-11_texas.pdf

Pediatric glioma stem cells: biologic strategies for oncolytic HSV viral therapy.
Front Oncol. 2013;3:28. doi: 10.3389/fonc.2013.00028. Epub 2013 Feb 28.
http://www.ncbi.nlm.nih.gov/pubmed/234506

Are there survivors?

Are there any survivors of DIPG- even just one?

This is the fervent plea of so many parents whose children were just diagnosed with this terrible tumor. A  search of the internet yields conflicting information.  Here are some statements I have found:
*There are no long term survivors of DIPG.
*There are long term survivors.
*The long term survivors are atypical.
*If there are long term survivors then they were mis-diagnosed.

What is a parent to think?  Who do you believe?   Why are these statements so divergent?  Is there an answer one can trust on survivors?

My short answer:
*There are long term survivors of DIPG (meaning more than 5 years).

*Most of the reported long term survivors are atypical in some way especially the very young (under 3), prolonged symptoms before diagnosis or atypical features on imaging- but not all.

* It is hard to say that a long term survivor was misdiagnosed since the diagnosis is based on imaging. The assumption has been if the lesion is uniformly diffuse and encompasses a large part of the pons then the lesion is a glioma.  It is then called a DIPG.   Since we have not have routine biopsied it is impossible to know the histology so all might not be gliomas.   However, one can tell on imaging if the lesion is diffuse, intrinsic and pontine.   It might be semantics but it seems hard to be a misdiagnosis per se but rather currently there is an inadequate understanding of these lesion.

I am virtually certain that the parents of prolonged survivors were given the exact dismal prognosis as those parents whose children had only a short time.   I think it is extremely unfair to then go back and tell these parents that "well, it wasn't really a DIPG".   It seems more valid to say that we don't understand these tumor.  Some unpredictably and inexplicably do better than the vast majority of others.

So, why can I be so certain that there is at least one term survivor?   One doesn't need to take my word for it.   I would recommend viewing a 2009 video of a top St Jude researcher, Alberto Bronsicer.
http://justonemoreday.org/DIPGConference/NewClinicalTrialsfromStJude.html
(go in to 15:49 minutes)

Transcript:
I swear to you- typical brainstem glioma.  I work her up- was one of my first patients at St. Jude.  Full blown findings.  We have spectroscopy.  You name it.  This is the MRI to show and 5 years later.  She has some sequela of her treatment.  One thing I point to all my parents- she never had complete response.  A partial response.   You see changes there 5 years later and she is out and about.

So yes, there is at least one long term survivor of what appeared to be a very typical DIPG.  Unfortunately, the vast majority of children with these tumors will follow this path but for those that find hope in just one- here is one.