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Thursday, November 3, 2011

DIPG - Current Status and Future Strategies

The September 27th issue of journal Child’s Nervous System included a review article evaluating where we are with the treatment and research of diffuse intrinsic pontine gliomas.  These authors performed an extensive literature review particularly looking at clinical trials, evolving molecular biology and new therapeutics.

 In their review they found-
  • Radiation is the only treatment that has consistently shown clinical and radiographic improvement.  Approximately 70% of the children receiving radiation will have clinical improvement and 30-70% will have radiographic improvement.
  • Multiple studies using a combination of radiation and another agent with generally unimpressive results.  Such agents have included RMP-7/carboplatin, topetecan/cisplatin, tamoxifen,  vincristine/vp-16, cisplatin, temozolomide,  vandetanib, and tipifarnib.  However, the vandetanib study showed that those patients that had a higher plasma VEGF level to start had a longer progression free survival whereas those patients that has increasing levels of VEGF with treatment had a shorter progression free survival. (Original vandetanib study- http://www.ncbi.nlm.nih.gov/pubmed/20921456 )
  • “No single chemotherapeutic agent alone or in combination, either in a neoadjuvant oradjuvant setting, has proven to increase disease-free survival or alter overall survival in these children with primary or progressive disease.”  This has included avastin and irinotecan which has had some success in adults. 

The prognosis has remained dismal for more than two decades.   This ‘virtual standstill’ for improved prognosis is leveled at:
  •  The lack of biologic knowledge about these tumors.
  •  Assumptions that adult and pediatric high grade gliomas are the same.
  •  The poor drug access to the tumor because of the blood brain barrier.  
  •  The lack of experimental models.

Recommendations included:
  1. A shift in treatment paradigm to include a diagnostic biopsy to “identify key molecules of unique signaling pathways which could provide clues to potential targets.
  2. Development of preclinical (i.e., mouse) models.
  3.  “The need to design phase I study with routine sampling along with CED of therapeutic agents is imperative in these fatal tumors.”
  4. “Further exploration of these different imaging modalities needs to be continued, and should facilitate better understanding of tumor architecture and metabolic profile as well as to provide more accurate prediction of extent and duration of response following radiation and adjuvant  therapies.”
  5. Evaluation of immunotherapy, gene therapy and other innovative techniques.

Diffuse intrinsic pontine glioma-current status and future strategies.
Childs Nerv Syst. 2011 Sep;27(9):1391-7. Epub 2011 Apr 30.

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