CONFRONTING CANCER; Low-Dose Regimen Offers a New Alternative in Chemotherapy
By DENISE GRADY
Published: April 9, 2002
At the age of 14 months, Melanie Joy McDaniel is doing the wonderfully normal things that every parent looks forward to: she eats grown-up food, stands by herself, toddles around the house while hanging on to the furniture. With every passing day she is becoming more of a buddy to her brother, Jonah, who is almost 3.
''Just looking at her, talking to her, you'd never know, unless you saw the big scar,'' said her father, Paul.
Melanie has a malignant brain tumor that two operations could not fully remove. Last fall, after her second operation, doctors offered a standard course of chemotherapy, but warned Mr. McDaniel and his wife, Amy, not to expect too much.
''There is no known cure for this type of tumor,'' Mr. McDaniel said; Melanie's cancer is called an ependymoma. ''I think there are no long-term survivors.''
The chemotherapy would have to be given intravenously, and side effects would make Melanie sick. The McDaniels were reluctant to put her through it.
Their doctor at the Dana-Farber Cancer Institute in Boston, Mark Kieran, offered another option, an experimental approach. Instead of traveling from their home in Londonderry, N.H., to the clinic for big doses of chemotherapy every few weeks, the McDaniels could treat Melanie at home, giving her low doses of several drugs every day by mouth. There would be no needles, and the side effects were expected to be mild.
Unlike standard chemotherapy, which is given in high doses to kill as many cancer cells as possible, the lower-dose regimen is meant to attack the blood vessels that feed the tumor. Tumors create their own supply lines by secreting substances that stimulate the formation of new blood vessels, and researchers suspect that frequent low doses of certain drugs may disrupt the growth of those new vessels, starving the tumor.
But, Mr. McDaniel recalled, the doctors said, ''We don't know if it works.''
He and his wife decided to give Melanie the experimental treatment. ''It won't save her, but it may help other people,'' Mr. McDaniel said. Then he added, ''Maybe it will save her.''
The treatment includes small daily doses of standard chemotherapy drugs, and two other drugs that have been found to inhibit the formation of new blood vessels, called angiogenesis. One is Celebrex, usually given for pain and inflammation. The other is thalidomide, notorious for causing birth defects when pregnant women took it in the 1960's. Researchers later discovered that thalidomide stunted fetuses' limbs by inhibiting the growth of blood vessels.
The idea of testing chemotherapy and other drugs in this continuous, low-dose way is still very much in its infancy, and doctors say it should be offered only to people who have no other options -- people like Melanie who have advanced tumors that standard treatment cannot cure, or those for whom standard chemotherapy has quit working.
''You would never use something this experimental in someone who clearly has another curative option,'' Dr. Kieran said. ''But if you've exhausted everything that's known, we have advantages here. These drugs are available, and well tolerated.''
Dr. Kieran and his colleagues are conducting two clinical trials, one for children with incurable cancer, and one for adults with brain tumors. Other centers are also studying the approach. In some clinics, women with advanced breast or ovarian cancer are being given smaller, more frequent doses of chemotherapy to reduce side effects.
Dr. Kieran said he had received ''literally 1,000 calls from doctors around the country'' asking about low-dose therapy for patients who had run out of treatments, and he said many doctors were trying it.
Ultimately, doctors hope to find out whether low-dose treatment may help other cancer patients, not just those who are considered terminal.
''Maybe you can give chemotherapy in a way that is much kinder and gentler, and paradoxically it may work just as well or even better, maybe through this ability to cause an anti-angiogenesis effect,'' said Dr. Robert S. Kerbel, a tumor biologist at the University of Toronto. ''We have a long ways to go before we can definitively prove that. But it's an interesting possibility that deserves to be scrutinized in preclinical studies and clinical trials.''
The treatment goes by different names: some call it low-dose, some prefer ''metronomic'' because of its regularity and others describe it as ''anti-angiogenic.''
This approach to treatment is based on a decade of research in animals, and on something that occasionally occurs in people: sometimes, when a tumor becomes resistant to chemotherapy and high doses stop working, lower doses of the same drug can shrink the tumor, at least temporarily. Doctors have known of cases like this for years, without understanding them. Some, but not all, believe angiogenesis plays a role.
The animal research started at Children's Hospital in Boston in the laboratory of Dr. Judah Folkman, who for 30 years has been studying the role of angiogenesis in cancer.
Dr. Folkman's team had found that angiogenesis was essential to the survival of many tumors. And they knew that many chemotherapy drugs, in addition to killing tumor cells, also fought angiogenesis.
But if the medicines stop angiogenesis, the researchers thought, chemotherapy should work better than it does. Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so even if cancer cells become drug resistant, the medicines should still be able to shrink tumors by destroying their blood supply.
But many tumors defy chemotherapy: they shrink temporarily and then grow back.
In the early 1990's Dr. Timothy Browder, who worked with Dr. Folkman, suggested a reason that chemotherapy was not stopping angiogenesis. Chemotherapy is usually given in a big doses, with breaks of several weeks between doses to let the body recover. During the breaks, Dr. Browder said, the tumor's blood vessels could grow back. He suggested that giving chemotherapy more often, at lower doses, might prevent the regrowth of blood vessels, and kill the tumor or at least slow its growth.
Dr. Browder began testing his ideas in mice, using cyclophosphamide, a common chemotherapy drug also known as Cytoxan.
In mice that had very drug-resistant tumors, standard treatment with Cytoxan caused only a small delay in tumor growth. But when the drug was given more often, in smaller doses, it delayed the tumors more, though they did eventually grow back.
When an experimental drug -- TNP-470, which stops angiogenesis -- was added, the combination eradicated drug-resistant lung tumors in 32 out of 38 mice. Tests showed that the drugs were destroying the tumors' blood vessels.
About the same time, researchers at the University of Toronto, inspired by discussions with Dr. Folkman, were doing similar studies in mice, using low doses of a chemotherapy drug, vinblastine, combined with an experimental drug that fights angiogenesis, DC101. The group, led by Dr. Kerbel, also found that the combination therapy could wipe out tumors.
The two research teams had reports published simultaneously in April 2000 -- Dr. Browder's team in the journal Cancer Research, and Dr. Kerbel's in The Journal of Clinical Investigation.
In their report, Dr. Folkman and Dr. Browder warned that their findings did not mean doctors should alter conventional treatments, which, they wrote, ''have led to a profound increase in the survival of children with cancer and have improved the survival of adults with certain types of cancer.''
Dr. Kerbel said it was especially important to study low-dose therapies now because they were being used increasingly in clinics. Doses, timing and combinations all need to be worked out. Doctors need to find out whether the treatments can make patients live longer, and, if they do, whether tumors will eventually outsmart the drugs and find ways to survive even without angiogenesis.
Melanie McDaniel has been on her low-dose regimen for about five months.
''Since November she's had three M.R.I.'s, and there's been no change,'' Mr. McDaniel said. ''Everything is stable.''
It is good news that the tumor has not progressed. But Mr. McDaniel met another patient on the same regimen who was stable for only four months before the tumor started to grow. Melanie is due for another M.R.I. this month.
''You treat her like a normal child,'' Mr. McDaniel said. ''You can't sit here and think about it all the time or you'd go nuts. You can't be thinking she might not make it past 3.''
Photo: Amy and Paul McDaniel, with children Melanie and Jonah, chose experimental treatment for their daughter, who has brain cancer. (Rick Friedman for The New York Times)