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

New Trial- MGMT Cancer Gene Therapy Trial

One of the huge problems with chemotherapy is that it beats up normal cells- especially bone marrow.   The toxicity limits how far the doctors can increase dosages before it is just too much for the body.  One novel idea is to try to make the normal bone marrow cells more resistant to chemotherapy.  This is exactly what researchers are trying to do with a gene therapy which effects MGMT.  This will allow for increasing doses of temozolomide.

Dr Geoffrey McCowage at The Children's Hospital of Westmead in Sydney Australia has spent the last 15 years developing a trial which removes bone marrow stem cells, genetically modifies the NA repair protein and then reinserts them into the patient.   The hope is that this modification will allow a patient to withstand escalating chemotherapy while better targeting the tumor.   In fact, this is more than theory.    This first of kind therapy for brain tumor kids is open in trial.

This Phase 1 intervention is open to several different types of brain tumors including brainstem glioma of diffuse pontine type  and all the following recurrent tumors- medulloblastoma, ependymoma, atypical teratoid rhaboid, high and low grade glioma.

Erin is the first child enrolled.   You can read at-
 http://www.news.com.au/national-news/south-australia/brave-erins-inspirational-battle-against-cancer/story-fndo4dzn-122658419720
Last month she had reached a year from diagnosis- and in the picture she looks great.

The trial is being funded by the Kid's Cancer Project (formerly Oncology Children's Foundation),  Sporting Chance Cancer Foundation and the Australian governmental funding agency, The Department of Innovation, Industry Science and Research.

Erin is hoping to raise $50,000 for The Cure Starts Now for DIPG research.

Note- A similar trial seems to be open in the US at the NIH for adult glioblastoma patients.

References:

Brave Erin's Inspirational Battle Against Cancer-  http://www.news.com.au/national-news/south-australia/brave-erins-inspirational-battle-against-cancer/story-fndo4dzn-122658419720

MGMT Cancer Gene Therapy Project- http://www.thekidscancerproject.org.au/Research/Gene-Therapy-Trial.aspx

Cancer Gene Therapy Project (Westmead Research site)- 

http://www.chw.edu.au/research/groups/oncology/research_groups/cancer/

Australian New Zealand Clinical Trial Registry (ANZCTR)-

https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12612000535875

NIH Adult Trial with Newly Diagnosed GBM- http://www.clinicaltrials.gov/ct2/show/NCT01269424

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

PBTC Phase 2 Study Results for Temozolomide/06-Benzylguanine

An abstract was released ahead of print for a phase 2 Pediatric Brain  Tumor Consortium study on recurrent/progressive high-grade gliomas and brainstem gliomas utilizing the combination of temozolomide and 06-benzylguanine (06 BG).  The study was initially put up on clinicaltrials.gov in January 2006.

O6-Benzylguanine and Temozolomide in Treating Young Patients With Recurrent or Progressive Gliomas or Brain Stem Tumors

http://clinicaltrial.gov/ct2/show/NCT00275002?term=06+temozolomide&rank=10

The thought was that the two agents may work differently to stop tumor growth and that combined chemotherapy might kill more cells.   Temozolomide is an alkylating agent that interferes with DNA replication.  This mechanism of action has seemed dependant on the ability to methylate DNA primarily at the N7 of 0-6 position on guanine.  Some cells were found to be able to repair this DNA damage.  The hope that O6 BG might overcome some of that repair issue.

Of the 41 children evaluated, 16 had brainstem gliomas.  There were no sustained objective responses with any in the brainstem glioma group, however, one patient had long term stable disease of more than 6 courses (28 day course). 

It was concluded that this combination “did not achieve target response rate for pediatric patients with recurrent or progressive high grade glioma or brainstem glioma.”

A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study   
http://www.ncbi.nlm.nih.gov/pubmed/21968943