Understanding the Issues with DIPG Biopsy
Michael H. Handler, M.D.

Michael H. Handler, M.D.

Associate Professor
Director, Pediatric Neurosurgery
The Children's Hospital

Contact Information:

Address:  13123 E. 16th Ave. 
Aurora, CO   80045
Phone:
     720-777-6100
E-mail:     handler.michael@tchden.org

To schedule an appointment:  720-777-6100 (option 1)
Clinical Interests
:  Pediatric Neurosurgery, 
Congenital Malformations, Brain Tumors, Epilepsy Surgery, Neuroendoscopy

For More Information on Michael H. Handler, M.D.:
www.ucdenver.edu

Understanding the Issues with DIPG Biopsy An Interveriew with Dr. Michael Hander

Dr. Handler is the Director of Pediatric Neurosurgery at Denver's Children's Hospital. The physicians at Denver brought he issue of biopsy for children with DIPG to the forefront in April 2009 during an FDA meeting. The transcript, minutes and slides from that meeting are available at- http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/PediatricAdvisoryCommittee/ucm116530.htm

Dr Handler's slides from that meeting reviewed the results in the literature regarding stereotactic brainstem biopsy.
http://www.fda.gov/ohrms/dockets/ac/09/slides/2009-4431s1-05.pdf

Denver along with 19 other US institutions have come together to participate in the first US trial for DIPG children using upfront biopsy for molecular stratification of treatment.
http://www.clinicaltrials.gov/ct2/show/NCT01106794?term=DIPG&rank=5

The following is a series of questions answered by Dr. Handler so that parents can come to better understanding of what is entailed in this new direction for DIPG clinical trials.

1. How do you select the area of the tumor to take the sample, and how can you be sure that is representative of the tumor as a whole?
Dr Handler: We choose by the area that seems most accessible. Remember that by definition these will look very uniform, so no particular benefit to select one area over another. However, as the "typical one" is still "allowed" to have an area of enhancement and central necrosis, we would select both the margin of that area and the center as well

2. How big is the incision?

Dr Handler: Typically, a couple of cm. Need to get through muscle at the back of the neck to get to bone, so the depth requires a little length of incision.

3. What is the function of the areas of the brain that the needle must pass through to reach the tumor?
Dr Handler: Cerebellum controls for smooth movements and balance. The middle cerebellar peduncle, the anticipated approach, can be penetrated safely with a brain canula safely, with no expected consequence.

4. Is this procedure done with imaging technology in "real time" - i.e., can the surgeon see the brain, the tumor and the needle throughout the procedure?
Dr Handler: Yes and no. the image guidance system stores an MRI image of the brain. The "real time tracking" shows the position of the needle in relation to the stored image of the brain. It does not update with new images as you go.

5. What is the "track record"? I presume that this is in adults. What are the physiological differences which might make this more risky for children?
Dr Handler: I am not sure where I talked about a "track record" per se. I can say that there are nearly 400 documented stereotactic brain stem biopsies in the literature, both in kids and adults. a very substantial number of the series are in kids alone, though I do not have the exact number at my fingertips. There is no difference in the technique between kids and adults other than the thickness of the skull and the amount of pressure that is applied to the pins which stabilize the head in position so that there is no movement during the insertion of the brain biopsy instrument (="needle" colloquially)
6. What is the potential therapeutic benefit of biopsy for the individual patients, given the state of knowledge right now?

Dr Handler: It would allow appropriate diagnosis in the context that these tumors, on biopsy or autopsy, have proven to be at least 4 different types. Treatment of, for example, PNET and glioblastoma is different in other parts of the brain, so should appropriately be different here as well. In addition, determining the molecular genetics of a tumor may suggest that certain of the more "experimental" therapies might be more beneficial for an individual patient than another of the experimental therapies. Right now, we throw them all into the same bag, and may be muddling our results so that we cannot understand what is happening.

7. How long would a child need to be in the hospital, assuming no complications?

Dr Handler: Assuming no complications, as long as they are now.

8. Would the child need a PICU to recover?

Dr Handler: Need is relative. We would likely put a child in the PICU overnight whether he/she wakes up neurologically unchanged or not. The ICU stay after most brain tumor operations, including this type, is to make sure that IF there is a late neurological deterioration it is picked up quickly. Most kids will stay only overnight.

9. Would the children need to be intubated for the procedure?

Dr Handler: Yes, but then, all of these kids are intubated for the purpose of putting in a permanent IV for long term therapy so not an "extra" anesthetic, just an extension of one that would happen anyhow.

10. How long before the child could resume that child's maximum "normal" activities, given existing tumor symptoms? For example, could the child go swimming in three days?

Dr Handler: In theory yes, though in practice, these kids still are receiving high dose steroids, and are in hospital for stabilizing and planning for radiation therapy, and most have deficits which would preclude swimming anyhow. Kids don't get back to their prior baseline for a while, after radiation has begun.

9. I have seen reference in the studies to "transient morbidity" in some patients. How long is "transient", generally, and what constitutes "morbidity"?

Dr Handler: Typically, worsening of an existing weakness, visual disturbance, balance issue, or the like. Usually a few days. So for example, a child with an atypical tumor who was at our hospital recently and biopsied a few days ago, became more somnolent and had worsened weakness of the arm and leg, which then cleared three days later.

11. Could this interfere with starting radiation on time?

Dr Handler: In theory yes. In fact there is no hard and fast rule about when to start radiation. So, for example, one would wait till after a weekend to start radiation, anyhow, just because unless there is a potential for imminent demise or catastrophic irriversible neurological collapse, we don't do radiation emergently. Families may take a while to decide how to proceed, or until a child who has hydrocephalus has had a drain converted to a shunt, or whatever, can delay therapy without apparent compromise.

12.Might an "open" biopsy yield more information about a child's tumor? What are the relative risks of the two procedures?

Dr Handler: Yes, certainly. This is the focus of an old debate, and a question for which there is no right answer. There is no doubt that the more tissue that is taken out, the more confident one can be that the specimen is representative of the tumor as a whole. And the more opportunity one has to do additional tests on the tissue. However, a stereotactic biopsy involves a very small incision, a small hole in the bone, and in the covering of the brain the dura, and minimal disturbance of the brain equals "minimal morbidity." An open biopsy of this deep lesion requires a large incision in the muscles of the neck, which hurts, a much larger opening in the bone, and greater risk of bleeding and so on. The brain has to be manipulated to gain access to the area of the biopsy, which introduces risk from pressure on the brain. Then, the more tissue you take out, the greater the risk of a greater degree of neurological deficit and the greater the chance that the deficit would be permanent.

13.What might be the consequences to the child if the sample taken is not representative of the entire tumor? If so, how? If not, why?

Dr Handler: The data shows that to be relatively small, but the risk we accept in exchange for the lesser surgical risk and the decreased time of recovery after the procedure. For example, if the sample showed that the tumor was a low grade glioma, would the treatment be different than if the tumor were a GBM? Yes If so, how? Less toxic therapy with smaller risk of treatment related complications. If not, why do the biopsy? Historically, the observation has been that "they all die anyhow" so why do it. It is not really clear that that is right. We have all seen kids who by that formula should have died quickly, but did not, presumably because of the inaccuracy of the initial diagnosis.

14. If there was a sampling error and the wrong treatment was started, how would you later be able to determine that there was an error, and change course?

Dr Handler: Rebiopsy if the clinical situation warrants it, just as we do in tumors elsewhere in the brain.

15. Might a sampling error result in a completely wrong diagnosis ie – biopsy says ependymoma, but the tumor really is a glioma?

Dr Handler: Again, the idea is that the biopsy should drive the therapy. We can only work on the data we have. And we will always have to balance the risk of taking more tissue and thereby doing more damage, with the risk of making the wrong diagnosis (which can sometime happen even with open operations)

16. Is there any way to tell at this point how frequently sampling errors occur?

Dr Handler: Not really. Most stereotactic biopsies are accurate enough that we keep doing them, rather than to abandon the technique.

17. In addition to the atypical brain stem tumors, are there any types of patients who might particularly benefit from biopsy? For example, brain radiation to very young children is considered particularly risky. Could biopsyhelp the doctors and parents determine whether it was safe to delay radiation?

Dr Handler: Yes. One would never irradiate a small child with a low grade tumor. That child would get a different chemotherapy.

18.Given the state of knowledge now, if you were faced with a scan showing a "typical" DIPG, what would your treatment recommendations be:

With no biopsy? Irradiation, possible experimental therapy
With a biopsy showing that the tumor was low grade? Low grade chemo regimen
With a biopsy showing that the tumor was not a glioma, but a PNET? Radiation and chemo for PNET
With a biopsy showing that the tumor was a GBM? Radiation, possible experimental therapy