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A report on a new cancer treatment and a teenage girl who volunteered for it.
LEE ANN MITCHELL:
She loved life. She was very sociable, had a lot of friends– very popular in school until all of this happened.
Last year, Kelley Mitchell lost her battle against cancer. But before the 16-year-old died, she agreed to try a highly experimental cancer-fighting therapy, which produced amazing results for a short period of time. Now, less than a year after her death, Mitchell's case has inspired important clinical trials in similar therapies. For Mitchell's parents, Donald and Lee Ann, the difficult journey began five years ago when they became worried about the leg pains bothering their normally healthy 11-year-old daughter, Kelley.
We took her to a regular family doctor.
Three times, because it wasn't getting any better.
And they looked each time and said, "hey, look, you know…"
We've got to check for something. There's… She's in too much pain. She's up at night crying, her leg hurts, there's too much pain here. So Donny made the pediatrician send her for an x-ray.
Mitchell was diagnosed with a form of bone cancer called Ewing's Sarcoma. Over the next five years, she endured chemotherapy, full body radiation, and a bone marrow transplant. She came down with a second round of Ewing's sarcoma, and fought that as well.
So, then, in may of '98 she had relapsed with the Ewing's again. She was very ill. We were losing our daughter, and my prayer at that point was "God, give us more time. I'm not ready to say goodbye."
Kelley Mitchell was being treated by pediatric oncologist Dr. Chris Rossbach in St. Petersburg, Florida. He says she understood the gravity of her condition.
DR. CHRIS ROSSBACH, All Children’s Hospital:
She was devastated. For a young girl, a very smart girl who had experienced so much and knew so much– about cancer in general and her particular tumors and the therapies– i don't think she saw a way out.
With nothing to lose, Rossbach looked to the latest cancer research and found articles on angiogenesis. It's a process that was first described by Harvard University's Dr. Judah Folkman. 30 years ago, Dr. Folkman realized that a cancer cell cannot grow unless it develops blood vessels that bring in oxygen and nutrients. That process is called angiogenesis. Dr. Folkman then developed drugs to stop the process of angiogenesis– angiogenesis inhibitors. The first two drugs were angiostatin and endostatin. He explained how they work in this 1990 interview.
DR. JUDAH FOLKMAN:
One of the drugs we're working on stops the blood vessels from growing in, so the tumor is sitting there, but since it can't connect up to the blood vessels, it's very hard for it to send cells out into the bloodstream. It's the same as if you build a house and now you want to hook up to the sewage system or to the water system. If you have no pipes, there's nothing you can do to get into the main system.
The treatment created a media splash when a respected scientist told the New York Times in 1998 that "Judah is going to cure cancer in two years." The story also created skeptics, as well as an intense interest in research on angiogenesis inhibitors. Researcher Dr. Gerald Soff from Northwestern University took Folkman's work a step further. Soff discovered that by combining two already existing drugs, the body could make enough of its own angiostatin to inhibit tumor growth.
DR. GERALD SOFF, Northwestern University:
In other words, we can give the two drugs to patients with cancer and the… Their own plasminogen and their own plasma is converted to angiostatin directly in their bodies.
So their own bodies become little drug-making factories?
DR. GERALD SOFF:
Exactly right. And we call it… I called it an angiostatic cocktail.
Dr. Rossbach wanted to try Dr. Soff's therapy on Kelley Mitchell, even though up to then results had only been seen in rats. But he needed approval from his hospital to use such an experimental treatment.
DR. CHRISTOPHER ROSSBACH:
I wrote up a little proposal. I approached our hospital; the institutional review board, who I believe thought I was crazy.
He did get approval from his hospital board. He was blunt when he talked with the Mitchells about their daughter's chances with the new therapy.
There would be no guarantees. None whatsoever. So we would not know how Kelley would respond to it, but if we were interested in trying an experimental drug– it had never been tried on any other human being– was it something we would think about doing?
Kelley Mitchell said yes.
She looked me right in the eye and said, "mom, even if i die taking this treatment, if they get enough research from me taking it to ever save another child from dying of this disease, i'm willing to do it."
Based on Dr. Soff's research, Dr. Rossbach treated Kelley with the so-called angiostatic cocktail. He used two different drugs already approved by the F.D.A. One was Captopril, a commonly used blood pressure medication; the other, Urokinase, a clot- busting drug used for heart attack patients. He hoped the cocktail would work as it had it Dr. Soff's lab. If it did, in theory, it would raise the level of angiostatin in Kelley's body, which would then go to work to stop the growth of her tumor. It had worked in mice, but it had never been tried in humans. And so in September of 1998, Kelley Mitchell began taking the angiostatic cocktail.
And all of a sudden something started to happen. And she came to me one Sunday night about six weeks after the treatment had started. We had just done the third treatment, and she had a really bad boil starting in her groin area, on her left side, which is where the tumor was. It was huge. So they admit us to the hospital, they put a drainage tube in it, and they send it down– once it starts draining into the bag– they send it down to the lab. The next morning, Dr. Rossbach comes into our room, and he is like a kid in a candy store, is the only way I can describe the look on his face. He says, "it's dead tumor tissue." The tumor was gone. There was nothing there.
Dead tumor tissue meant Kelley Mitchell's cancer cells had been killed.
It was unbelievable. Because that was clearly not what we had expected. We had thought, well, maybe the tumor will not grow quite as fast, maybe it will shrink a little bit here or there, or maybe if we just find things that we envision as slightly better. This was a completely different picture.
Kelley got to live the life of a normal teenager, even get a drivers license.
And a new car for her 16th birthday, a special gift from her parents.
There was one point in time where the mother actually asked whether she could go jogging, which was an incredible question for me as a doctor of a patient who was supposed to die soon.
While Kelley Mitchell's recovery was amazing, it was unclear how big a player the angiostatic cocktail actually was.
To be honest, I can't tell you that i'm convinced that it worked the way we think it might have worked, because she clearly did not have just one therapy. It is entirely possible that all her initial response was because of the other therapies, as short and abbreviated and minimal as they were — I have to argue that before you create hope in a lot of people that there's a new therapy out there that is effective, that you really have to use it on more than one individual.
University of Chicago medical school researcher, Dr. Ralph Weichselbaum, is investigating the effects of combining angiostatin with radiation therapy. Kelley Mitchell's response could have been related to the 15 doses of radiation she got shortly before she was given the angiostatic cocktail. Weichselbaum was excited about Mitchell's results, but remains eager for the necessary clinical trials.
Wasn't it your research coming to life?
DR. RALPH WEICHSELBAUM, University of Chicago Hospital: Don't I wish? Realistically, this is somewhere between magic and witchcraft, and fundamentally should not be done. The only way you can access this kind of a treatment is in a controlled, clinical trial where the physicians have a scientific hypothesis about what they want to test, where the patients have appropriate informed consent, and where you can actually have some valuable idea.
Four months after Kelley Mitchell was tumor-free, she stopped taking the angiostatic cocktail. In case of a relapse, doctors stored enough for two more treatments. But a key ingredient in Mitchell's angiostatic cocktail was taken off the market because of problems in manufacturing. Almost a year later, a young cancer patient that Kelley Mitchell had known from the hospital had a relapse. The young girl's mother reached out to Dr. Rossbach for Kelley Mitchell's remaining two cocktails.
When we found out the tumor had come back, we asked Dr. Rossbach about the medicine that he had used on Kelley Mitchell.
What was your reaction?
I wanted it for Karen.
And did you ask for it?
Kelley and I sat down and we talked about it. And she said, "Mom, I'm almost 16 and Karen's only 12. Let's give her a chance to live." I said, "Kelley, understand, please– understand– if your tumor ever comes back, this drug's not available now." And she said she understood but she wanted Karen to have the chance to live.
The treatment that appeared to work on Kelley Mitchell, had no effect on Karen Schoenberg.
Karen passed away at the end of October of '99, and Kelley still was doing good. She turned 16 on January 10. She was doing so good, and then February rolled around, and she started limping again. And she walked off, and my heart sunk, because I knew. The limp was really bad and I knew.
The cancer had returned. Dr. Rossbach said he could try and find a synthetic version of the drug in the angiostatic cocktail that had been taken off the market. But Kelley Mitchell decided she'd had enough.
She said, "Mom, I'm not trying anything else. I'm going to go home to the Lord now."
Dr. Rossbach respected Kelley Mitchell's decision.
What this kid has gone through is just unbelievable. If you count the two relapses of the Ewing's, she's had five cancers in her life, in a life that only was 15 or 16 years long. It was intellectually interesting… would have been interesting to pursue that, to see: How much more can we get out of this kid? But I did not think it was right for me. I think I would have felt selfish.
Do you think if she had continued with the therapy she might be alive?
To answer that question is sticking my neck out a bit. I dream that she would have. I pray that it will work if we start it again, but we don't really know that yet. We have to do a series of patients and a series of trials and answer the question scientifically. If the angiostatic cocktail really pans out, and it'll take some serious effort to determine that, I mean, she will be one of the most important cancer patients that have been treated.
Largely because of the results seen with Kelley Mitchell's treatment, Dr. Soff himself began clinical human trials of the angiostatic cocktail. He currently has 12 patients in the trial. And there are several other key drug trials under way. The father of angiogenesis research, Dr. Judah Folkman, has just presented his results from phase one trials on his angiostatic inhibiting drug called endostatin. Phase one trials are done to make sure a drug is safe.
Folkman's drug not only showed virtually no side effects, but also showed tumor shrinkage in some of the patients. Human trials on Dr. Weichselbaum's therapies may begin within the year. So far he has shown tumors in mice shrink faster when angiogenesis inhibitors are used in combination with radiation than when used alone. It's not just a medical foot race, it's a financial foot race as well. Dr.'s Folkman, Soff, and Weischelbaum all have partnerships with drug companies involved in the testing of angiogenesis inhibitors.
The stakes in the race are huge. The financial analysts are talking about something like $20 billion or $30 billion a year in sales for successful angiogenesis inhibitors.
But experts in the field caution against raising unrealistic expectations, then point out that there are many approaches to treating cancer, stopping angiogenesis is just one of them.
So I look at this as another rung on the ladder or another arrow in our quiver. And, obviously, I hope it turns out to be more than that– i hope it does turn out to be the magic bullet.
Results from the first group of patients in Dr. Soff's human trials are expected this summer, one year after Kelley Mitchell's death.
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