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

FDA Public Hearing on Biopsy of Children with DIPGs- Part 3

Stereotactic Biopsies

Although typical DIPGs (without focality or exophytic components) can not even be partially resected because the tumor tissue intertwines with normal tissue in an area that houses most critical functions of the body in a small space, it is possible to biopsy these lesions via an open or a stereotactic technique. Dr Michael Handler, pediatric neurosurgeon from Children’s in Denver, presented an overview of stereotactic biopsy technique and a review of the literature specific for brainstem biopsies.

Stereotactic neurosurgery is a minimally invasive procedure where tumor imaging is used in conjunction with external reference points on the head (either with a frame or frameless via fiducial markers) to develop a three dimensional image to precisely localize a location within the brain. The idea of this technique has been around for more than a century. Horsley and Clarke used a frame on experiments with monkeys in analyzing the cerebellum back in 1906. Stereotactic biopsies for humans really did not take off until the 1970’s with the advent of CT scans which allowed for detailed imaging and 3D localization. The technique rapidly adapted to MRIs when this technology became readily available.

Dr. Handler pointed out that during the 80’s there was a rapid expansion of experience. It was found that-

• The safety of this technique became well established.
• This technique was applicable to deep lesions in the brain.
• Questions about sample adequacy subsided
• It was found to be an unquestionably effective technique.

Dr. Handler presented the results of 13 different studies on stereotactic brainstem biopsies to try to give background on the ability to get diagnoses from a small sample, morbidity and mortality. Some of the most interesting articles include-

Brainstem stereotactic biopsies sampling in children.Neurosurgery 2006 Feb;104 (2 supplement): 108-114In this study 10 children underwent frameless biopsy. All samples were diagnostic and there was one case of transient diplopia.

Stereotactic biopsy of brainstem masses: decision analysis and literature review.Surg Neurol 2006 Nov; 66(5): 484-90This was a metanalysis of 378 patients. The results included-- 6.6% transient complications,. 1.5% permanent new deficit and a 0.5% mortality.

Prospective feasibility study of outpatient brain biopsies. Neurosurgery 2002 51 (2): 358-361In this series of 76 patients which were slated for outpatient brain biopsies only 3 got admitted. One was for IV antibiotics after an infection developed and the other was a failed biopsy (a hard lesion which the needle could not penetrate).

“Prospective feasibility study ofIf the reader is interested, this would be most easily reviewed from Dr. Handler’s slides referenced at the bottom (slide 10-17).

Dr Handler ended his presentation with a quote from Dr. Andrew Brodbelt commentary in the British Journal of Neurosugery last October regarding this controversy.“It surprises us treating adults with brainstem tumours that there appears to be reluctance in the paediatric world to perform biopsies….We owe it to current and future patents to biopsy brainstem tumours.”

References:

April 27th, 2009 FDA joint PAC/ODAC public meeting on DIPG BiopsyAll presentation slides including Dr. Handler’s are available at the site http://www.fda.gov/ohrms/dockets/ac/09/slides/2009-4431s1-00-Index.html

A Short History of Stereotactic Neurosurgery

Brainstem stereotactic biopsies sampling in children.
Neurosurgery 2006 Feb;104 (2 supplement): 108-114

Stereotactic biopsy of brainstem masses: decision analysis and literature review.
Surg Neurol 2006 Nov; 66(5): 484-90

Prospective feasibility study of outpatient brain biopsies.
Neurosurgery 2002 51 (2): 358-361

Commentary on diffuse brain stem glioma in children
Br J Neurosurg. 2008 Oct;22(5):625.

FDA Public Hearing on Biopsy of Children with DIPGs- Part 2

To Biopsy or Not to Biopsy- How Did We Get Here?

Dr Foreman gave the dismal background on DIPG treatments. The only treatment known to help prolong life in these children is radiation; however, attempts to intensify radiation treatments have not improved outcome. In addition, chemotherapy has been tried both before and after radiation without success. In fact, the UKCCSG stated, “This approach should be abandoned as toxic and without benefit and with toxicity.” Even high dose chemotherapy with autologous bone marrow rescue has failed.

Given the terrible track record and significant lack of specific tumor biology knowledge, why do we not biopsy these tumors?

The most influential paper that changed the standard method of diagnosing diffuse intrinsic pontine gliomas from biopsy to MRI was published by Albright in 1993 [1]. This paper reviewed the results of a brainstem trial (CCG-9882). In this paper the authors recommended that biopsies not be done because they added nothing to the diagnostic precision of MRI. Dr Foreman noted complication rates were not included as part of the justification for this position, and there was actually no surgical mortality in this study.

In a commentary on the Albright paper, Dr Fred Epstein (a pioneer in the field of pediatric neurosurgery – especially in the brainstem) stated, “Routine biopsy should be relegated to neurosurgical history.”

This is where we are today. As opposed to adults where biopsy of diffuse brainstem masses is common as there is are a greater variety of etiologies, biopsy of pediatric DIPGs is currently only recommended for atypical cases. Yet more and more, authors are publishing such comments as, “Given the lack of efficacy of conventional drugs, a better understanding of the biology of this tumor is the key to more targeted therapy.” [2]

In an attempt to address whether science has progressed sufficiently to warrant a change in philosophy toward DIPG biopsy, the committee debated the following scientific question:
“Based on your discussion, has the state of the science in drug targeting research progressed to where there is a reasonable expectation of success in identifying drug candidates to move into early phase clinical trials for DIPG?”

The vote was 16 yes, 7 no and 1 abstention. (The reason given for this abstention was inadequate knowledge of this subject.)

Reference-
1. Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children's Cancer Group.
Neurosurgery. 1993 Dec;33(6):1026-9; discussion 1029-30

2. Brainstem gliomas in children and adults.
Curr Opin Oncol. 2008 Nov;20(6):662-7

3. April 27th, 2009 FDA joint PAC/ODAC public meeting on DIPG Biopsy-Slides

FDA Public Hearing on Biopsy of Children with DIPGs- Part 1

On Monday April 27th, the FDA held an open public meeting to discuss the scientific and ethical issues involved in developing drug treatments for children with diffuse pontine glioma.

Biopsying children with diffuse intrinsic pontine gliomas has become increasingly controversial. Clearly there are physicians that strongly hold the opinion that there will likely be no movement to cure these usually fatal tumors until tissue is obtained. Those that take this position tend to feel that the state of the art advances in neurosurgery and genomics have made it possible for DIPGs to be treated in the same way that almost all other brain tumors (as well as virtually all other cancers in the body)- with pathologic diagnosis.

This debate has gained even more attention because of a recent French trial for newly diagnosed diffuse intrinsic pontine glioma patients in which biopsy was mandatory in order to be able to participate. Of the 24 patients, all survived and two had transient neurological problems. In addition, two patients were found to have low grade tumors and were treated differently specifically because of the biopsy results. With respect to the remaining 22 high grade tumors, there was no change in therapeutic intervention as a result of biopsy.

Although there was no specific protocol or agent placed in front of the committee, the obviously increasing interest in the change of direction with this tumor caused the DIPG biopsy issue to be placed before the committee. At this time there appears to be a minimum of two or three potential US protocols on the table that include biopsy of DIPG.

It was stated that biopsies may be routinely recommended for atypical lesions. This is a clinical decision, not an ethical question.

In addition, biopsies performed as part of a determination for therapeutic intervention were also not to be part of the conversation. By definition these would be therapeutic biopsies. However, it was noted by some that the results from selecting agents based on molecular markers has been marginal in the field thus far.

The ethical question brought before the committee was:
“Assuming a reasonable expectation of scientific success, should children with DIPG undergo a non-therapeutic brain biopsy to advance the study of possible drug targets (i.e., for research purposes only)?”


References:

Stereotactic biopsy of diffuse pontine lesions in children.
J Neurosurg. 2007 Jul;107(1 Suppl):1-4

April 27th, 2009 FDA joint PAC/ODAC public meeting on DIPG Biopsy- Slides