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.

Results of St Jude Phase 1 Trial Published

The results of the St Jude Phase 1 trial using a combination of small molecule inhibitors, vandetanib and dasatinib,  have just been published electronically (ahead of print) in the journal Clinical Cancer Research.

In a look back at DIPG history, this is a really a new kind of trial.   In the past many trials have been radiation and a single agent.  I think we can say with some certainty that DIPG tumors will need more than a single agent for cure- especially for targeted therapies.  These tumors are complex and have so many pathways that it is likely that the tumors will be able to get around a single agent.

In addition, there seems to be rational basis to chose these agents specifically for DIPG.  Vandetanib has a combination of effects on different targets but is a potent VEGF inhibitor.   This is known to be a player in GBMs (and as been said here before when studied histologically most DIPGs have been found to be GBMs).   Dasatinib has its effects at PDGFRA (platelet derived growth factor receptor alpha).  Several recent publications have highlighted the PDGF pathway as being key in the development of DIPGs.

In this study, 25 newly diagnosed children were started on oral dasatinib daily at the start of radiation.   Eight days later oral vandetanib twice a day was added.     Overall the treatment was tolerated well.

• The M:F ratio was 12:13.
• The age range was 2.3 years to 17.2 with a median age of 5.8 years.
• The median treatment time was 184 days.   
• The most significant toxicity was diarrhea.
• Myelosuppresion (drop in blood counts) was seen in three children.
• Two of the children had tumor biospies.  
• There were 12 post mortem tumor donations.  
• All patients progressed on treatment.   
• The one year overall survival was 52% + 10%.
• The 2 year survival was 9% + 6%.  
• The two patient who were on treatment for more than 2 years had typical clinical and radiologic appearance of DIPG

An interesting part buried in the article text was the approach to radiation.  The radiation field encompassed the tumor and a 2cm margin in the transverse (across) and caudal (down) direction and a 3cm margin in the superior direction.  The increased from 2cm to 3cm in the superior direction was based on preliminary results on progression patterns of DIPG patients.   Of note, one patient had extensive bilateral thalamic extension requiring whole brain radiation.

Three of the young children developed symptomatic radiation necrosis in uninvolved brain areas.  Although there was no institutional knowledge of other patients treated with more than standard radiation fields developing radiation necrosis in uninvolved areas, it was felt that the larger margins may have lead to symptomatic radiation necrosis.   Thus the authors do not recommend to use of enlarged radiation fields.

Another interesting finding was that the researchers showed "for the first time that CSF exposure of vandetanib and dasatinib in humans is modest".   They point out that CSF levels is often used as a surrogate marker for brain penetration but that this assumption is not necessarily valid particularly in places where there is a blood brain barrier disruption.  They also point out that although the dasatinib CSF level was low that it did reach sustained levels "similar to those causing significant inhibition of other drug targets.

Additionally, the researchers looked at plasma angiogenic factors (seeing what factors are in the blood). Surprisingly, increased VEGF in this study was associated with longer overall survival whereas in a prior study it was associated with shorter survival.  The hypothesis is that this might be because of an improved inhibition of alternative pathways because of the combination.  Regardless of the reason, it seems to me that we don't understand plasma factor levels yet.

Despite the continued poor results for DIPG clinical trials, there were some interesting findings in this trial.   There is hope the drug testing (such as what we should see with the pre-clinical consortium) might find new promising targets or drug therapies.

Note-

This work was supported by the U.S. National Institutes of Health Cancer Center

Support (CORE) Grant P30 CA21765, by the Cure Starts Now Foundation, by

AstraZeneca, and by the American Lebanese Syrian Associated Charities (ASLAC).

References:

Phase 1 Trial, Pharmacokinetics and Pharmacodynamics of Vandertanib and Dasatinib in Children with Newly Diagnosed Intrinsic Pontine Gliomas

Clin Cancer Res. 2013 Mar 27. [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/pubmed/23536435

Clinical Trials Entry   

http://clinicaltrials.gov/ct2/show/NCT00996723?term=dipg&rank=2

Atypical "DIPGs" Not all Gliomas

This Japanese article electronically published in Childs Nervous System makes the case that although MRIs have been the basis for diagnosis for DIPGs since the 1990s,  "the accuracy of MR imaging baded diagnosis has not been fully confirmed".  This article goes on to say that there have been several reports indicating that some of these diffuse intrinsic brainstem lesions have been found to be other tumors rather than gliomas.  These have included  PNETs, ependymomas, gagliogliomas, rhabdoid tumors and pilocytic astroctyomas.   These other pathologies have been particularly found in those tumors that have an atypical appearance.

The authors decided to perform biopsy for pediatric intrinsic pontine lesions with atypical for DIPG findings on MRI.   Atypical MRI findings were defined as:
a) extended beyond the pons
b) had a well-defined, localized enhancing part with in a high intensity lesion on T2-weighted images.

Seven patients underwent open biopsy because of diffuse lesions in the pons that were not typical for DIPG. Four patients had a focal enhancing lesion, five had extension beyond the pons and two had both.  
The biopsy revealed:
5- diffuse brainstem glioma
1- PNET
1-pilocytic astrocytoma

There were no biopsy related deaths or intra-operative complications.  One child has transient worsening of hemiparesis.

The 12 year-old child harboring a PNET presented with double vision, unsteady gait and a facial palsy.  His tumor had focal enhancement but no extension beyond the pons.  The child received craniospinal radiation with tumor boost and chemotherapy as would be done for a supratentorial PNET with marked shrinkage.  At 13 months the tumor recurred near the genu of the corpus collosum.  This lesion had radiosurgery.

The 7 year old female with a pilocytic astrocytoma presented with difficulty speaking.   Her tumor did not enhance but extended beyond the pons into the right cerebellar peduncle and pons.  She did not have radiation but rather carboplatin and vincristine.   At the time of article submission the tumor had been stable for 9 month.

So, of the 5 children found to have high grade gliomas three of these had areas of focal enhancement and four had extension outside the pons.   The presenting symptoms included only right hemiparesis in one, only a facial palsy in one and lethargy in one.   Only two children had 2 symptoms of the typical triad.  One child had gait disturbance and facial palsy and the other had gait disturbance and hemiparesis.  Of these 5 high-grade glioma children, four of the tumors regrew within 7months( range 3-7 months).  Two of these children had died at the time of publication.

From this very small sample it seems there is no way to predict by MRI pathology without biopsy in atypical diffuse pontine tumors.   The article concluded that "an open biopsy of intrinsic brainstem lesions is considered safe and effective for selecting appropriate course of therapy".

References:
The efficacy of biopsy of intrinsic brainstem lesions for decision making of treatment.Childs Nerv Syst. 2013 Feb 3. [Epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/23377758

Biopsy Consensus Statements on DIPGs

Over the last few years there have been rapid change in treating and understanding pediatric brain tumors.   Per this recently electronically published article in Neuro Oncology these include :
1) Brainstem tumors are now considered to be safe targets for either stereotactic or open biopsy;
2) Age is a major factor interacting with tumor behavior (progression risk);
3) Recent research identifying new biologic markers of tumor classification and new druggable targets for trials has provided and opportunity to explore novel approaches to therapy.

In  February 2011, the second Consensus Conference on Pediatric Neurosurgery (CPN 2011) was held in Paris, France with the objective to establish a new consensus on surgical approaches to pediatric gliomas.   Statements on high grade gliomas, hypothalamic chiasmatic gliomas and diffuse intrinsic pontine gliomas were developed.  Statements  were disseminated to the 92 participants for a vote.  A statement was accepted if there was more than 70% of votes in favor of the statement.

Here are the final statements regarding DIPGs.
Typical DIPG
Biopsy of  a typical DIPG (defined by a short history and typical imaging findings) is justified when the patient is part of an ethically approved clinical study in which the tissue obtained will be used to investigate or inform the role of biological markers after treatment selection or molecular tumor grading.

Atypical Pontine Region Tumors
(A) Biopsy by an experienced pediatric neurosurgeon is indicated to confirm the diagnosis and guide therapy,
(B) An atypical pontine region tumor would be considered separately from classic DIPG for therapy or research purposes.

Authors of the final consensus paper included:
* David A Walker- Nottingham, United Kingdom
* JoFen Liu- Boston, USA
* Mark Kieran- Boston,  USA
* Nada Jabado- Quebec, Canada
* Susan Picton- Leeds, United Kingdom
* Roger Packer- Washington, USA
* Christian St. Rose - Paris, France

References:
A multi-disciplinary consensus statement concerning surgical approaches to low grade, high grade astrocytomas and diffuse intrinsic pontine gliomas (CPN Paris 2011) using the Delphi method.
Neuro Oncol 2013 March 15 [epub ahead of print]
http://www.ncbi.nlm.nih.gov/pubmed/23502427

Typical Versus Atypical- What does that mean?

At one time all gliomas of the brainstem were thought to have an equally poor outcome.   Over the years (especially with better imaging), we have come to find not all brainstem gliomas are the same.—  and actually some brainstem gliomas (tectal gliomas, cervicomedullary gliomas, focal gliomas) were found to have a favorable prognosis.  However, the vast majority of brainstem gliomas- perhaps 85%- were diffuse and intrinsic and pontine.   These DIPGs, diffuse intrinsic pontine gliomas were all though to the same terrible life expectancy.

Now it has been found that not all DIPGs are the same.   Some children initially diagnosed with diffuse intrinsic pontine gliomas unexpectedly had prolonged survival.   There seems to be increasing understanding that some of these tumors are typical with the predicted short survival; then there are others that are atypical and might have longer time.

So what makes a DIPG atypical versus typical?  

 Well, there have been developing imaging appearance and clinical presentation criteria that may put a child on one side or the other. 

Typical Imaging-

1)   The tumor is diffuse without exophytic components or focality,   The tumor is mixed in through normal tissue like “sand in grass” or “pepper in jello”.

2)   The epicenter is located in the pons.  

3)   A majority of the base of the pons is affected.    Some trials require 50% while others require infiltration of 2/3 of the basis pons.

Typical Clinical Features-

1)   Age- So far seems to be written as more than 3 years of age to 18 or 21.  Younger and older patients with diffuse intrinsic pontine tumors are more likely to have prolonged survival.

2)   Clinical Symptoms Triad- Children at the time of presentation tend to have 2 out of 3 typical symptoms.   The typical triad includes a) ataxia/unbalanced gait, b) cranial nerve signs, and c) “long tract signs”- often weakness on one side.

3)   Symptom progression-Symptoms progress rapidly within one to two months from onset to diagnosis.

So, what difference does typical versus atypical make?   

Those with atypical radiographic appearance or clinical  features a may have increased survival.   This may be because these tumors are not high grade gliomas.  Thus, many DIPG trials are requiring biopsy for those children that are atypical.  If one is atypical a difference treatment course might be recommended.

It is likely better to know if a child is atypical before choosing a treatment course.   To get another opinion one can contact the DIPG Registry (http://dipgregistry.org/patients-families/second-opinion/)
or potentially contact a primary investigator of a DIPG trial (www.clinicaltrials.gov).

Note:  As we gain more understanding of diffuse intrinsic pontine tumors the categorization and definitions will probably change just as we have seen over the last couple decades.