Voices on Pediatric DIPG Biopsy- Mark Kieran MD PhD

Identification of Novel Biologic Targets in the Treatment of 

Newly Diagnosed Diffuse Intrinsic Pontine Glioma

ASCO 2012 Education Session Presentation

The third speaker on the 2012 ASCO session was Mark Kieran from Boston presenting "Identification of Novel Biologic Targets in the Treatment of Newly Diagnosed Diffuse Intrinsic Pontine Glioma".  Certainly Dr Kieran has been enduring in his passionate belief that non-treated tissue is going to be critical to the understanding and hopefully cure of DIPG.   He has worked much of the past decade to bring the standard of care for typical pediatric DIPG in line with advancements in neurosurgical techniques and cancer molecular biology research.  The video announcing that DIPG biopsy would be an educational session at 2012 ASCO much have provided a sense of satisfaction that this issue had reached prominence enough to be discussed at a significant cancer meeting. (click here to watch announcement video)

The first video I saw of Dr Kieran discussing this advancements in neurosurgery and cancer molecular biology research that makes DIPG biopsy possible and critical in understanding pediatric DIPGs was back in 2009.   The first international DIPG conference in Barcelona, Spain sponsored by the Alicia Pueyo Foundation included a presentation on this issue.  (click here for video)  The 2012 video shows how far we have come in the DIPG community as well as with cancer molecular biology.

Dr Kieran points out that the understanding DIPG biology is in it's infancy.    Few existing publications are on non-treated (biopsy specimens).  Treatment has the potential of significantly altering the genomics of a tumor.   However, there have been some consistencies:

* P53 loss/mutation is present in a significant number of tumors.

* The RTK-Ras-PI3K-Akt pathway is altered in a number of tumors. 

* PTEN loss might mean that mTOR might be a target.

* Hedgehog-dependent cancer stem cells might be a target.

Regardless of the ultimate biology of DIPG, we can definitely say that DIPG is different from both adult and pediatric high grade gliomas.   Treatment for kids with DIPG can not be based on these other tumors.

There is a caveat- just finding drugable targets might not alter the outcome with DIPG.  So for this approach has not changed the prognosis in adult GBMs despite a huge amount of available tissue.  We are at the beginning.   We don't know yet.   There is hope and optimism that this is a start. 

References:

From boos to hope: Challenging the dogma about deadly brain stem gliomas

http://childrenshospitalblog.org/from-boos-to-hope-challenging-the-dogma-about-deadly-brain-stem-gliomas 

Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma
http://www.ncbi.nlm.nih.gov/pubmed/22190243

Voices on Pediatric DIPG Biopsy- Nicholas Foreman MD ChB

The Ethics of Biopsy in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma

ASCO 2012 Educational Session Presentation

"If the the definition of insanity is doing the same useless thing with the same outcome, this is it."

....Dr Nick Foreman speaking on the negative results on dozens of trials in DIPGs with no biologic knowledge of the tumor

Dr Nick Foreman,  director of the pediatric neuro-oncology program at Denver Children's, presented the second lecture at the 2012 ASCO educational meeting  "Pontine Gliomas in Children:To Biopsy or Not to Biopsy".    Dr Foreman along with his colleague, neurosurgeon Dr Michael Handler, actively and aggressively challenged medicine's standard practice of not preforming biopsies in 10% of children with brain tumors when that tumor (DIPG) has been almost always fatal and no trial has shown any benefit for the tumor.  They argued that it was really unethical to continue to subject these patients to phase 1 trials to obtain toxicity and dosage data when one could not show any benefit from the dozens of trials previously.   These two physicians worked to have the American Society of Neurosurgery reverse the standard practice of not preforming biopsies for DIPG children.   

This 16 1/2 minute presentation is a personal account of the resistance encountered when developing DIPG research that stemmed from work done in 2004 in biopsies of pediatric supratentorial GBMs.  The 2004 work lead to a 2007 IRB proposal in which 10 children with DIPGs were to be biopsied (with parental consent) without treatment based on those biopsies.  This was pretty much exactly what France had already done and published results with no mortality and transient morbidity.  However, the local IRB could not make a decision resulting in an FDA hearing on the topic.  The results of the FDA panel was mixed so the initial proposal of 10 children being biopsied was rejected in favor of the current upfront biopsy trial that is underway.

Now that we have the biopsy trial open in the US  and 2011 Consensus Conference on Pediatric Neurosurgery specifically stated a standard regarding biopsy of typical pediatric DIPGs within clinical trials, we may now be past much of the controversy of the past decade.   Still, I think it is important to know the traumatic, tragic history of how this stagnated DIPG research.  

Dr. Foreman ends pondering a question on whether we "missed the boat" for DIPG children by failing to openly recognize that in experienced hands DIPG biopsy is not more dangerous than in other areas of the brain.    

If the majority understood that the 1993 paper recommending "routine biopsies be relegated to history" was referring to MRI's accuracy of diagnosis and not on DIPGs surgical risk/safety, could we have moved faster in the current age of cancer molecular biology to have known about such abnormalities as the histone mutation much earlier.  Perhaps we could have been further along on a cure.

References:

Nicholas Foreman, Pediatric Neuro-Oncologist

http://www.coloradocancerblogs.org/conversation-dr-nicholas-foreman/

Interpretation of magnetic resonance images in diffuse intrinsic pontine glioma: a survey of pediatric neurosurgeons

http://www.ncbi.nlm.nih.gov/pubmed/21721895

Slides of Dr Foreman's presentation in 2009 to the FDA

http://www.fda.gov/downloads/AdvisoryCommittees/.../UCM150193.pdf

Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brainstem gliomas:  a report from the Children's Cancer Group

http://www.ncbi.nlm.nih.gov/pubmed/8133987

Voices on Pediatric DIPG Biopsy - Stephanie Puget MD PhD

Is Biopsy Safe in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma?

ASCO 2012 Educational Session Presentation

One of the most controversial subjects in pediatric DIPGs over the last decade has been the biopsy issue.  This has been the topic of discussion in private, editorials and even an FDA open hearing.   At the 2012 ASCO meeting in Chicago there was an educational meeting chaired by Mark Kieran MD PhD entitled "Pontine Gliomas in Children:To Biopsy or Not to Biopsy".   To me the greatest thing about this session is that it was taped and made available on the internet.   This allows for those who were not in Chicago last year for ASCO to have a better understanding directly from some of the key international figures regarding this extremely important matter.

Stephanie Puget MD PhD, a French neurosurgeon, started the session with a 20 minutes presentation on "Is Biopsy Safe in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma?"  Dr Puget is a central figure in the landmark French DIPG clinical trial with upfront biopsy.   Since the 2007 publication it seems that Dr Puget has had speaking engagements on both sides of the Atlantic to discuss DIPG biopsy.  This was the first time though that I was able to actually hear her speak.

Dr. Puget started her talk with five questions.
1) Is biopsy needed for a DIPG diagnosis?
2) If not, why do biopsy for DIPG?
3) Can DIPG biopsy be safely preformed?
4) Can DIPG biopsy be preformed by everyone?
5) What can be done with the biopsy specimens?

The short answers-
1) No, it is made by MRI in conjunction with clinical symptoms.
2) Analysis of the tumors may lead to relevant biomakers and hopefully better treatment.
3) Yes.
4) No.
5) Allows for molecular studies (including whole genome sequencing and mutational analysis) and cell lines (of which they had 5 stem cell lines a the time).

During the presentation she reviewed the results of the French Biopsy experience.   From 2002 to 2012, 92 biopsies were preformed with no mortality and only 5 patients experience morbidity.  Four of these patients had transient problems including cranial nerve palsies or weakness.  One child had a permanent hemiparesis but also was found to have disease progression.  She said "it could be considered as safe as a stereotactic biopsy in the supra-tentorial space in a well-trained neurosurgical team".

She also addressed a few technical considerations: frame versus frameless surgery, choosing a route and choosing a biopsy site.  Please note at approximately 14:30 minutes there are real videos of biopsy in children.  At 18:30 minutes the size of the biopsy samples is shown as well as pre and post procedure MRIs.

For those interested in the pediatric DIPG biopsy issue, this is a very informative 20 minute presentation from someone who as been on the frontline.  

Reference:
Is Biopsy Safe in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma?
Stephanie Puget MD PhD
http://meetinglibrary.asco.org/content/66763

DIPG in Istanbul

Recently a publication came out in the journal Child's Nervous System retrospectively reviewing patient characteristics and outcomes in children treated  for DIPG over a 13 year period (February 1999 to May 2012) at Cerrahpassa Medical Faculty and Oncology Institute in Instanbul, Turkey.

In this review there were 26 girls and 24 boys with a median age of 7.  The median duration of symptoms - including cranial nerve palsies, motor  disability and/or cerebellar dysfunction- was 30 days.  The diagnosis was made by a multidisciplinary tumor board which included a a pediatric oncologist, radiation oncologist, neurosurgeon, and radiologist in the multidisciplinary tumor board.

Radiation was part of all the children's therapy although only twelve received radiation alone.  The other children also received some form of chemotherapy with radiation. In 17 patients a radiosensitizer (either vincristine or cisplatin) during radiation and followed by CCNU and vincristine after radiation.   After temozolomide became available this agent was used both during and after radiation for the remaining 21 children.

These three groups were analyzed regarding outcomes:  group 1-radiation alone; group 2-vincristine/ciplastin; group 3- temozolomide.   In this study,  children in either chemotherapy group  did better than those that had radiation alone.    Ten of the children in group 2 were alive at 2 years and 3 at 3 years.  Three children in group 3 were also alive at 3 years.   

Interestingly 3 children in the temozolomide group had biopsies and were found to have pilocytic astroctyomas!

Fo me it is hard to know exactly what caused these two chemotherapy groups had better survival.   It would seem that the 3 children with pilocytic astrocytomas were included in the analysis.   The authors also said that there were improvements in radiation techniques over time which could have been a factor.  Thus children who had radiation alone were the earliest patients in the review.  Also it seems over type palliative care, PEG tubes and shunts became more common in that institution which may have played a role in the statistics.

Positive results of temozolomide with DIPG have not been replicated in other countries.   Still, this article has significance to me to show the increase interest in DIPG around the world as well as the improved treatment for children with cancer.   It was also good to see the conclusion that "the complex biology of DIPG renders an unselected single-agent approach less likely to be effective. Instead, a multi-targeted approach seems to be required to improve the prognosis".   Hopefully we will see increasingly available multi-targeted options for children with DIPG.

Reference:
Pediatric diffuse intrinsic pontine glioma patients from a single center
Childs Nerv Syst. 2013 Apr;29(4):583-8. doi: 10.1007/s00381-012-1986-3. Epub 2012 Dec 8.
http://www.ncbi.nlm.nih.gov/pubmed/23224361

Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma (France)
http://www.ncbi.nlm.nih.gov/pubmed/21858607

Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group
http://www.ncbi.nlm.nih.gov/pubmed/21345842

Prospective evaluation of radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma (India)
http://www.ncbi.nlm.nih.gov/pubmed/19647954