Case Report- Two Children with Prolonged Survival

During time period between June 2008 and June 2009, Children’s Healthcare of Atlanta treated three children diagnosed with DIPG with radiation followed by temozolomide and avastin.   Two children were still alive at 37 and 47 months from diagnosis.  The other child had progression free survival for 12 months followed by rapid deterioration with death at 14 months from diagnosis. 

Here is the recent case report of these two children who have surpassed the 3-year mark since diagnosis of a DIPG and were still going strong at the time of publication.

Patient 1- was described as an 11-year-old male with a 2 month history of weakness on the left side as well as walking and swallowing difficulties.   The initial MRI showed a 4cmx3.5cmx3cm non-enhancing tumor of the pons and medulla.  

Patient 2-was described as an asymptomatic 7-year-old female who was found to incidentally have a 3cmx2.3cmx2.6cm pontine mass after head trauma.   She was observed closely with serial MRIs.  Two MRIs showed increased tumor size and at 8 months from initial presentation she deteriorated developing a facial palsy, right sided weakness and hydrocephalus.  The tumor was 4.2cmx4.3x3.8cm with new focal areas of enhancement.

The children were treated with temozolomide 200mg/2d/d for 5 days ever 28 days and avastin 10mg.kg.dose every 14 days.   In both patients a 65% decrease in tumor size was seen.   No steroids were needed after 10 weeks from radiation.   The therapy was tolerated well.  At publication both children were doing well and continuing on treatment.  The paper notes that the boy was going to school and playing soccer at 37 months.  

 (Note- the actual paper has several MRI images provided both initially and later for both children.)

The authors speculate that the combination of temozolomide and avastin might deliver more temozolamide to the tumor because avastin might normalize the tumor vasculature.    As support for this theory the authors point to cilengtide altering perfusion which allowed for increased temozolamide delivery  for gliomas.    Perhaps avastin has a similar effect.

An additional advantage of this combination might be the decreased need for steroids.

The authors recommend consideration of an expanded DIPG clinical trial with this combination.

By the way, the female child appears to be atypical both in presentation and focality in her tumor.   On the other hand, the male child seems to have a very typical presentation for DIPG.

Reference:

Prolonged survival after treatment of diffuse intrinsic pontine glioma with radiation, temozolamide, and bevacizumab: report of 2 cases.

J Pediatr Hematol Oncol. 2013 Jan;35(1):e42-6.

http://www.ncbi.nlm.nih.gov/pubmed/23249962

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.

Clinical Trial Update- Arsenic Trioxide (ATO) with Radiation in the Newly Diagnosed (Phase 1)

On March 3^rd, the Journal Neuro-Oncology electronically published the results of the phase 1 trial using arsenic trioxide (ATO) in combination with radiation for newly diagnosed pediatric high-grade gliomas.   This phase 1 trial, exclusively opened at Johns Hopkins (primary investigator Kenneth Cohen), was first submitted to clinicaltrials.gov in November 2004 and was completed in January 2011.    As a phase 1, the aim was to determine toxicity and dosing information--not effectiveness against the tumor.  

Rationale:   Arsenic trioxide affects cells in a different way than radiation.   In mice, ATO has shown destruction of the tumor vasculature and near-complete blockage of blood flow to the tumor.   This has resulted in central tumor death (necrosis).   The hope was that ATO would kill the poorly perfused, hypoxic, radio-resistant areas of a tumor while radiation would kill the tumor in well-oxygenated areas.

Format:  The format was to have groups of 3-6 patients receive escalating doses of arsenic trioxide until the MTD was established.  Each child received radiation once daily for 5 days a week for 6 weeks.  A child also received arsenic trioxide over 1 hour with radiation.   The first group received the ATO only once a week.  Each subsequent group had another day of the week added until the last group received ATO with every radiation treatment.  A total of 24 children entered the trial.   Those that progressed during radiation or family chose to stop treatment was removed from the study.  Twenty-one children had evaluable results. 

Results:  The trial included 12 DIPGs, 4 AAs and 5 GBMs.  Because children could receive additional therapy after 30 days from radiation, no response assessment was done.   The study does note that all children died of their tumor.   With DIPG the median time to death was 10 months (range 2-22 months).    There was no dose limiting toxicity.

Conclusion:  The article concluded that arsenic trioxide could be given with each radiation treatment.

 Interestingly, the article states that there have been a number of recent preclinical studies that have shown an effect on cancer stem cells trough an effect on Notch and Sox2.   Other research has shown that the hedgehog pathway might be antagonized and thus be helpful in other tumors as well (such as Sonic hedgehog driven medulloblastomas).  Although there is one adult glioma study using arsenic trioxide in combination with temozolmide and radiation on clinicaltrials.gov, there are no pediatric glioma studies open using arsenic trioxide.    The question now is whether there will be a phase 2 trial.

For those families that participated in this trial- thank you.   This work provides important information to move forward in trying to find a cure for DIPG.  Even if it doesn't provide the cure hope for, research tends to stimulate research.  There is much, much more research into DIPG than when when this study initially opened in late 2004.  People are searching for a cure.

References:

A phase 1 trial of arsenic trioxide chemoradiotherapy for infiltrating astrocytomas of childhood

http://www.ncbi.nlm.nih.gov/pubmed/23460318

Arsenic Trioxide and Radiation Therapy in Treating Young Patients with Newly Diagnosed Gliomas

http://clinicaltrials.gov/ct2/show/NCT00095771?term=arsenic+trioxide+glioma&rank=3

The Clinical Trial Process

http://www.dukehealth.org/health_library/health_articles/the_clinical_trial_process