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Lighting up brain tumors

Al's Comment:

This is one of my pet peeves about the USA FDA.  This treatment can help surgeons remove more of the tumor safely, and it is approved in Europe, used on thousands of patients safely. The FDA refuses to allow it's use here because they admit it is effective in allowing more of the tumor to be removed safely, but they question if that is a benefit.    They want a large randomized trial to be done comparing overall survival with patients who use this vs those who use a placebo.  I know that is one trial I would not be referring patients to. It is unethical and unnecessary.   

  I love the FDA - they understood the need to approve Avastin and the Novocure system even when they only showed a small benefit.  Now that they are approved and being used in combinations - they are showing better progress.   It is just in cases like this where FDA policy goes against common sense.



Posted on: 08/26/2013

Lighting up brain tumors

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Posted: Monday, August 19, 2013 5:25 pm

CLEVELAND, Ohio (Ivanhoe Newswire) -- Sixty-nine thousand people will be told they have a brain tumor this year. For people with the most aggressive forms, they’re expected to live less than five years after receiving the diagnosis – one major problem for surgeons, not being able to get the entire tumor out. Now, doctors are able to light up the tumor and see them better than ever before.

Judy Morrill walks four miles every single day with her dog Emma, and her husband Jim by her side, even the most deadly form of a brain tumor, called a glioblastoma, couldn’t slow her down.

“I just made up my mind that I was going to go forward and not backward and make the best of it,” Judy Morrill, told Ivanhoe.

She had one surgery to remove most of the tumor, but with this type of cancer, the cells can spread like fingers throughout the brain.

“We can never get all the tumor cells out,” Doctor Michael Vogelbaum, M.D., Ph.D. of The Cleveland Clinic, in Cleveland, Ohio, told Ivanhoe.

Now surgeons at The Cleveland Clinic are using a drug used to treat skin cancer, called 5-ALA, to literally light up cancer cells in the brain.

“It is converted primary by tumor cells into that substance that glows,” Doctor Vogelbaum explained.

Judy had a second surgery using 5-ALA, and doctors removed more of her tumor. Judy is now 70 and looking forward to what this new decade will bring.

“I’m so lucky to be alive, last year, I didn’t think I would be here for my birthday and now I’m having one this year,” Morrill said.

Although 5-ALA is approved to treat brain tumors in Europe, and bladder cancer in the US, The Cleveland Clinic is one of the few hospitals in the country involved in a clinical trial using it.

Neurosurgeon, Michael Vogelbaum, MD, at the Cleveland Clinic, talks about a drug that was generally used to treat skin cancer is now helping surgeons find cancer cells in the brain by lighting them up.

How many patients do you treat with brain tumors?

Dr. Vogelbaum:  That’s a tough number to come up with. Personally I probably treat somewhere between a hundred and fifty to two hundred patients with brain tumors each year.

What’s the hardest part about treating someone with a brain tumor?

Dr. Vogelbaum:  For the types of brain tumors that I treat, which are mostly the malignant brain tumors, the hardest thing is that we don’t have a cure for the vast majority of them. The treatments we use we know help and they help to extend life, and if they’re used well, they help to maintain quality of life, but they’re not cures and we haven’t found a cure for most of the malignant brain tumors yet.

If I understand correctly it’s also very difficult, because if you don’t get all the cells out from the brain tumors they can grow back pretty quickly?

Dr. Vogelbaum: Well the truth in surgery for malignant brain tumors is that we can never get all of the tumor cells out. We take out the worst part of the tumor – we take out the part that is taking up space – that is pushing on normal functioning parts of the brain and creating pressure inside the head, which can be dangerous. We know if we can take out the highest grade tumors, if we can take out everything that lights up with contrast, we have good reason to believe that patients will live longer as a consequence of that. So that’s one of the major goals of the surgery. However, we’re not curing the disease with surgery alone. There is a microscopic infiltrative portion of the tumor that goes inches away from where we do our surgery; we know there are tumor cells out there.

Are these the types of tumors that almost look like they have fingers that grow through the brain?

Dr. Vogelbaum: That is one of the terms that’s used to describe infiltration. It’s really that the tumor cells are infiltrating within the brain matrix itself and coexisting with normally functioning brain until they grow to be a number where they start to impair function.

How do you see these types of brain tumors affect your patients?

Dr. Vogelbaum: Patients come to us with a variety of symptoms that had led to the imaging that showed that they had a brain tumor. One of the more common symptoms is a seizure out of the blue in an adult. Adults don’t develop seizures out of the blue for too many reasons. Sometimes people will have headaches that are different from the ones they normally have and that are progressively worsening. Sometimes they’ll present with new weakness or problems with their speech or language; sometimes the symptoms seem like a stroke, but actually strokes are far more common than brain tumors, but that can be one of the symptoms of having a brain tumor. So there’s a variety of symptoms.

Traditionally how would you image the brain to see where the tumor is?

Dr. Vogelbaum:  Years ago one of the great developments in this field was the use of CT scanning. That became a very important tool for seeing exactly where a tumor was located. Since then MRI has become available and it’s a much, much better tool for actually showing us the intricate detail that we need to see in order to understand what’s going on and to plan a surgery and to plan all of the treatment.

What’s the down side to MRI?

Dr. Vogelbaum: There really isn’t a downside to MRI. Some patients don’t enjoy going through an MRI because they have to be inside a fairly tight tube and it is a noisy environment for the scan, but that’s really the only downside to it.

Could it give you all the details you would need?

Dr. Vogelbaum: It gives us the details we need. In fact it is by far the best tool. There are a few times when we have to work with CT scan only and it’s really turning back the hands of time when we’re doing that.

But now you’re adding something to the MRI’s.

Dr. Vogelbaum: It’s not really adding to the MRI. It’s actually a separate imaging approach and it’s not diagnostic; it’s purely within the OR and during surgery.

You use the MRI scan as your road map for the surgery; then you get in to the surgery; how do know you’re getting everything?

Dr. Vogelbaum: For many decades before we had MRI, and even when in the initial years when we had MRI, the surgery was done based upon the surgeon’s understanding of anatomy and the ability to interpret the MRI and apply it to the patient in three dimensions, which is what we are train to do, but the truth is we didn’t have much to guide us. We made very large openings in the skull and then we had to try to figure out where the tumor was in real time. Of course the danger there is one could end up going in to the wrong part of the brain. So along came a new technology which was called Image Guided Navigation.

How did this new technology help?

Dr. Vogelbaum: It allowed us to use a preoperative MRI and register it with the patient when they were asleep in the OR. In other words, we could load the MRI in to a computer system that we had in the OR and show that system what the patient’s head position was; that allowed us to navigate using special tools, very similar to the way that one uses navigation in the car. It shows us where we are. And we could plan our surgeries that way and make smaller openings, go directly to the tumor; making it safer and a more effective operation.

Do you ever come across any problems during operation?

Dr. Vogelbaum: The problem is that during the operation the brain shifts, especially when there’s a large tumor, removing a lot of it; the brain shifts and we lose that registration. So one of the next innovations was the development of intraoperative imaging; starting with ultrasound and then CAT scans and finally MRI. That’s a great way to be able to do the surgery, obtain a new set of images while we’re there in the OR and then continue with an updated map. The problem is that’s a very expensive solution and also it interrupts the flow of surgery because we have to stop, cover everything and then perform the imaging. Each time we do that it can actually lengthen the operation by an hour, which is not such a great thing.

How many times would you stop a surgery?

Dr. Vogelbaum:  I try to do it with just one image set. One additional image set but sometimes it can be two, three, or even four. So that can add a lot of time to a surgery.  The newest innovation is the use of a fluorphor that is a substance that glows indicating where tumor cells are present and the substance is called 5-ALA or 5-aminolevulinic acid. This is a substance that is used therapeutically for certain types of skin cancer. It’s used in a process called photodynamic therapy. The 5-ALA is converted by enzymes that are normally present in cells into another substance which glows; it glows red when it’s exposed to blue light. Usually that’s used as a topical application and that’s the way it’s approved in the US.  In the case of using it as a way to find tumor cells, it’s actually mixed in water and then ingested before surgery.

You just drink it?

Dr. Vogelbaum:  Just drink it; it’s a very small amount of fluid that one has to drink. Then over the course of the next few hours it is converted primarily by tumor cells into that substance that glows under a blue light. The cancer cells do that conversion much more actively than normal cells. And then one can visualize the tumor cells as they turn pink or red while we’re operating once we shine blue light on them.

Is it hard without this liquid to tell the difference between normal cells?

Dr. Vogelbaum: When we’re removing the tumor there are parts of the tumor that are obviously, as we say grossly abnormal. It’s really at the margins where you start having the tumor cells blending in to normal surrounding brain where you can’t tell. Or it can be very difficult to tell where the limits are. One does not want to go too far, if you go too far then you’re removing normal functioning brain, which is what we all want to avoid.  On the other hand we don’t want to leave the contrast enhancing tumor behind because we know that’s associated with a worse outcome.

When we’re talking about these cells can you give us an idea about how small they can actually be?

Dr. Vogelbaum: They are on the order of microns; twenty to fifty microns in size. So that’s micrometers, that’s one millionth of a meter.

When did you start doing this procedure?

Dr. Vogelbaum:  We started using the 5-ALA here about a year ago. It has had limited use in the United States; it’s not actually approved, for this purpose, in the United States. It is approved in Europe, however and has been approved for a number of years now. 

Is there any risk to it?

Dr. Vogelbaum: There are some risks associated with the drug itself. That is it sensitizes all tissues to bright light. So we actually keep the patients in a reduced light environment over the course of about twenty four to forty eight hours, in order to avoid skin burns associated with that.

You drink this, are brain tumors like breast tumors where breast tumors can end up in your liver and different places?

Dr. Vogelbaum: Brain tumors do not spread outside of the brain most often. They spread within the brain. The same principles that apply to cancers outside of the brain, that is when they spread to other organs that’s a much more serious situation, well the same is true within the brain. When these tumors spread within the brain that’s a very serious problem. That’s the biggest difficulty we have in trying to find a cure for these tumors is that they do spread microscopically within the brain.

Is it the skin burning problem is what’s keeping it from being FDA approved here?

Dr. Vogelbaum: No that’s a minor issue actually and very few reports of that being an issue because we know how to manage that. The other risk associated with it however is that one might go too far and remove too much tissue. We know that there’s going to be microscopic disease left behind. You can actually see evidence of it when you’re operating using this because you see a pink glow that remains even when you’ve gotten to the edge of the contrast enhancing tumor. So that could take the untrained surgeon in to areas that they don’t normally want to go in to. Where there may be tumor infiltration in functional areas that are still functioning just fine. We don’t want to take those parts out.

How important is it to get these small particles though?

Dr. Vogelbaum: We’ll never be able to get them with surgery, that’s not ever going to be accomplished with surgical removal of tissue, because the microscopic infiltration is so far away from the tumor mass that we would end up having to remove important parts of the brain. We wouldn’t do that, that’s one of the goals of surgery, is to remove as much tumor as possible, but the other equally important goal is to preserve function. And if we chase the microscopic disease too far we’re not going to be able to achieve that second goal.

How is this helping patients? Is it buying them time, years, months?

Dr. Vogelbaum:  We have evidence that removal of the worst part of the tumor, the contrast enhancing part of the tumor is associated with an improved survival. So this helps us to be more effective at removing that part of the tumor and thereby giving the patients the best operation possible for extending survival.

When you saw Judy what was she like before surgery?

Dr. Vogelbaum:  Before she had a surgery done at another hospital where some of the tumor was removed, but there was still a lot of the contrast enhancing tumor left behind. She was neurologically normal. Based upon the location of the tumor, I felt that it would be possible to remove all of the contrast enhancing tumor without putting her at undo risk of having a neurologic decline.

So do you think this is something you will use on all your patients?

Dr. Vogelbaum: The only way one can use it currently in the US is with a special permission called investigational new drug approval from the FDA. And in getting that one has to provide a fairly detailed and narrowly focused investigational protocol to the FDA for them to approve. So the one that we have really restricts this to a certain group of patients who are going to be operated on; who have gliomas; these people are going to be operated on using intraoperative MRI. We’re actually comparing intraoperative MRI to 5-ALA in terms of extended resection.  So it’s not going to be for all of our patients, it’s going to be for ones where we think that we can remove all of the enhancing tumor safely.

What’s the next step for this?

Dr. Vogelbaum: There have been a number of efforts to try to see whether 5-ALA can be approved for general use in the US. My interpretation of the FDA’s stance, right now, is that the data from Europe are not sufficient in themselves to get approval in the US, despite the fact that it was approved in Europe. And that the FDA would like to see more evidence that a greater extent of tumor removal really causes a longer survival. That’s what they seem to be hung up on. That’s a very difficult thing to prove, because the best test of that is a randomized study and a study like that may not be ethical to do.

Could this be used for all cancers, does it highlight just brain tumors?

Dr. Vogelbaum: There are some other types of tumors that it does highlight. It’s actually also approved for removal of some types of bladder cancers, when it’s instilled in to the bladder and they can be visualized that way. So there are some other applications for it. But for it to be used in this way for brain tumors it’s still investigational.

This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.

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