2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Ethics of Biopsy in Children with Newly
Diagnosed Diffuse Intrinsic Pontine Glioma
Overview: To understand the ethical dilemmas that beset
this issue of biopsy in children with newly diagnosed diffuse
intrinsic pontine glioma, one must understand both the history
behind it and the current dominant interpretation of ethics
through the medium of the institutional review boards. It is
IN DIFFUSE intrinsic pontine glioma (DIPG), the stage
for the controversy over biopsy was set in the early 1990s.
The early optimism engendered by the often dramatic responses
to radiation had faded and the fatal nature of DIPGs
had become all too obvious. The morbidity from biopsy in
that era was low, but there was no apparent benefit in
looking at the tissue over diagnosis by radiology. Indeed,
histology seemed more confusing than radiology given that
tumor grade did not influence survival. 1 The standard diagnosis
then became the “typicality” of the scan. If the scan
was typical there was no need to biopsy. Oddly enough, this
standard method of making a diagnosis was never standardized
and there remained a huge variation in what was
considered typical or atypical. 2
DIPGs were then diagnosed by scan. Radiation was administered
as a standard therapy and the tumors would
shrink. The quality of life for many would improve for a few
months. However, all children with “typical” (and, indeed,
most with atypical scans) would die. Time to death was
stunningly uniform across all studies, with a median of 9 to
10 months.
Given the lack of curative therapy, the children with this
terrible disease became the subject of literally dozens of
phase I and II trials. These were passed easily by institutional
review boards (IRBs) because there was a “possibility”
of direct benefit. No IRB seemed to have reviewed the
increasing evidence, added by each consecutive trial, that
there was no benefit from these non–biology-directed phase
I and II trials. 3 Children with this terrible disease suffered
again and again from vomiting and diarrhea from yet
another fruitless trial. Perhaps more than 1,000 children
worldwide were entered onto these trials with no benefit and
no questioning from the IRBs.
By the turn of this century, DIPG deaths were making up
to 30% to 40% of the deaths in the pediatric neuro-oncology
program as prognosis improved for other brain tumors.
There had been an explosion of biologic information about
most pediatric brain tumors, but virtually nothing was
known about the biology of DIPGs. There were discussions
with parents and parental lead advocacy groups. A proposal
was made by me at the Children’s Hospital Colorado in 2008
to biopsy a limited number of children with all the costs
being borne by institutional money. In the proposal it was
stated that there was no direct benefit to the children
concerned, instead of saying the benefit was in the order of
phase I or II trials. The local IRB declined to approve it
citing federal regulations that procedures done on children
should offer the possibility of benefit if they were not
minimal risk. 4 The IRB asked for a panel of experts to be
assembled and this led to a national panel being assembled
by the U.S. Food and Drug Administration (FDA). Although
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By Nicholas K. Foreman, MD
also important to understand that this article represents the
author’s personal viewpoint. At a consensus meeting to discuss
the issue of biopsies in Diffuse Intrinsic Pontine Glioma
(DIPG) at the National institutes of Health held in the fall of
2011, there were a variety of opinions expressed.
the proposal was supported by most members of the panel,
the ethicists on the panel were opposed and the local IRB
rejected the proposal. 5
This brought up some interesting ethical issues by various
panel members and participants. I am going to give some
personal comments on these in the following sections
First, That There Has to Be the Possibility of Some
Direct Benefit to the Child to Allow a Procedure or
a Therapy That May Cause More Than Minimal Harm
This does not have to be quantified and may in fact be
immeasurably small (such as the continuing proposals for
non–biology-based phase I and II trials in this tumor).
Indeed, it would appear it could even be speculative. IRBs
(and apparently ethicists) considered surgical procedures to
be in a different class from chemotherapy regimens, although
the latter may inflict weeks of misery on a child. The
French data showing a low risk to the procedure was
insufficient in the view of the ethicists. 6
So, if one said that the biopsy would include looking for
v600e mutation of BRAF or a H3F3A mutation and that the
child could at progression be considered a candidate for
therapy targeting these mutations, this might pass muster—even
though there is no evidence these agents are
effective in childhood brain tumors.
Second, That Societal or Family Benefit Should Not
Be Regarded in a Discussion of the Ethics of
Performing Biopsy on a Child
One of the ethicists said that consideration of societal or
family benefit was more in line with European ethics than
American. The basis for this statement is difficult to find and
perhaps lies more in the interpretation of ethics. Family
members at the meeting said the death of their child seemed
in vain, that nothing was learned and more children would
go on to die as a result of this terrible disease. They felt that
both they and the child (when older) would have had comfort
from knowing that others would be less likely to suffer. One
of the panel members implicitly stated that the family had
no rights in this matter and could not consent to their child’s
undergoing a procedure without direct benefit even when
the child had a fatal disease. Some of the parents were
From the University of Colorado, Aurora, CO.
Author’s disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Nicholas K. Foreman, MD, Professor of Pediatrics, Seebaum-
Tschetter Chair of Neuro-Oncology, University of Colorado, 13123 E. 16 th Ave., B115,
Aurora, CO 80045; email: nicholas.foreman@childrenscolorado.org.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10