A New Approach to Chemotherapy
Doctors Try Lower Doses, Given Continuously, To Reduce Side Effects and Starve Tumors
By AMY DOCKSER MARCUS
Staff Reporter of THE WALL STREET JOURNAL
October 25, 2005; Page D1
In the battle against cancer, doctors are finding new ways to use an old weapon: chemotherapy.
The idea behind chemotherapy has long been that more is better. In order to kill the tumor, patients are traditionally given the highest dose they can tolerate. But because the drugs are so toxic, the process must be periodically halted for several weeks to allow the body to recover. Some doctors argue that this resting period can allow a tumor to rebuild the network of blood vessels that it needs to keep growing.
Now, these doctors are experimenting with a new approach, giving very low doses of chemo drugs for extensive periods of time, with no rest. The approach represents a significant shift in thinking because the target isn't the cancer tumor itself. Rather, the aim is to halt the underlying growth process. Because the method spares patients the toxic side effects of high-dose chemo, such as vomiting and anemia, it can be given continuously for the long term -- perhaps turning the cancer into a chronic, manageable condition.
Sometimes called "chemo lite" or "metronomic chemotherapy," the method is being studied at the Dana-Farber Cancer Institute in Boston, Cedars-Sinai Medical Center in Los Angeles, the University of Toronto and other centers. Doctors are reporting promising results in a handful of clinical trials on cancers that include brain tumors, non-Hodgkin's lymphoma, and breast and ovarian cancer.
The low-dose approach isn't widely accepted, however, partly because of fears that it may result in undertreatment and jeopardize survival. There is also evidence from lab studies that even in low doses, side effects such as suppressed immune systems do eventually appear over time. So far, the approach has been used in patients with advanced cancer who have failed previous therapies. For these patients, the lack of immediate side effects has improved their quality of life. But doctors have just launched or are planning some new trials for people with breast cancer, ovarian cancer and some pediatric cancers who have less-advanced disease but are at high risk for a recurrence.
The new method comes at a time when there is increasing hope that, when cancer can't be cured, patients at least can continue to live with the disease for many years. Newer "smart" drugs such as Tarceva and Iressa are designed to target only cancer cells, not normal ones, minimizing toxic side effects that make chemotherapy so hard to tolerate and creating the prospect that they can be taken for years, not months. New attention to some of the side effects of treatment, and an increasing understanding of the biology of cancer have also helped create excitement about one day making cancer a chronic condition, much like diabetes or heart disease is today.
Low-dose, continuous chemotherapy is also part of a rising focus in oncology on the process known as angiogenesis, whereby the body develops new blood vessels that can feed tumors. A number of drugs in development, along with some current smart drugs such as Avastin, also work as so-called anti-angiogenic agents that aim to choke off a tumor's blood vessels. Instead of solely targeting tumors, which vary greatly from person to person and organ to organ, these drugs also target the blood vessels that tumors need to grow. Some researchers believe this approach could ultimately be far more widely effective.
Keeping Growth in Check
Researchers believe the low-dose chemotherapy, which is being given in combination with anti-angiogenic drugs, may work because it keeps the development of blood vessels in check. It is able to do this because the less-toxic treatment eliminates the need for rest periods, which give blood vessels a chance to start growing again. Even tumors that had become resistant to standard chemo drugs still responded to the low-dose approach in studies, these researchers say, because the treatment stemmed the growth of new blood vessels.
"So much of our current cancer treatment depends on understanding the intricacies of a specific tumor," says Mark W. Kieran, a pediatric oncologist at the Dana-Farber Cancer Institute who has led low-dose chemo trials. With this new approach, Dr. Kieran said, "we're attacking the tumor's supply line."
Many doctors are trying different ways to give chemotherapy, such as changing dose schedules, with the goal of making the regimens more bearable. A traditional chemotherapy regimen may last about six months and includes high doses -- such as 1,000 milligrams of the chemo drug cyclophosphamide every three weeks. Some doctors have experimented with how to spread out the dose, giving a little less at a time, but every two weeks. But this new low-dose method typically involves a fraction of the standard chemo amounts. In a number of anti-angiogenic trials, patients were given 50 milligrams of cyclophosphamide every day, with no breaks.
In one of the first published reports from the current wave of human trials, Dr. Kieran and his colleagues at Children's Hospital Boston and St. Louis Children's Hospital in St. Louis, Mo., will report next month on a trial of 20 children with various kinds of cancer. In the trial, the children received a cocktail of drugs known to interfere with the angiogenesis process, including Celebrex and thalidomide, as well as low doses of the chemotherapy drugs cyclophosphamide and etoposide. Five of the 20 patients are still responding to the treatment, according to the paper, to be published in the Journal of Pediatric Hematology/Oncology. Dr. Kieran says even just a 25% response rate is significant because these patients had no treatment alternatives left.
One of those children, Michael Shelley, age 10, was diagnosed five years ago with a brain tumor called ependymoma. He had surgery but the tumor came back. He underwent a second surgery followed by radiation, but the cancer came back again. So Diane Shelley, Michael's mother, enrolled him in Dr. Kieran's trial. At one point, she says he was up to 16 pills a day, drinking huge quantities of orange soda in order to take the regimen, which he was on for a year and a half. Mrs. Shelley says there were side effects: Michael was very tired, and because his immune system was so suppressed he got massive warts on his hands that made it hard for him to write. They ended the treatment after he needed a transfusion because his blood count got too low.
But Michael recently had a brain scan and "it was clean," said Mrs. Shelley. He just signed up to play basketball and baseball at school. "Compared to what other kids go through for chemotherapy, the side effects were minimal," says Mrs. Shelley.
Dr. Kieran is working on a new trial, which will study 160 children at hospitals that include New York University Medical Center and St. Louis Children's Hospital. He pays for these trials in large part with private donations.
There have been arguments in the medical community that perhaps the drugs are actually killing the tumor cells themselves and that is why the regimen works. But Dr. Kieran and his colleagues note in their paper that three of the patients had previously been treated with high doses of the same chemo drugs and seen their cancers grow. Now on low, sustained doses of the drugs, their cancers weren't growing or in some cases had shrunk.
Not all trial results have been so promising. Ian Tannock, a medical oncologist at Princess Margaret Hospital and the University of Toronto, led a study of anti-angiogenic chemotherapy in kidney-cancer patients. He said that of the 30 patients, one saw his tumor shrink and two others were stable. Dr. Tannock, who believes anti-angiogenic drugs like Avastin are beneficial, called the low-dose chemo results "not remarkable." "I think it's a reasonable idea to test," he says, "but I don't see this as the wave of the future."
Sandra Fraley, 56, of Boston, has advanced breast cancer and has been on a low-dose daily chemotherapy regimen plus Avastin for a year as part of a current clinical trial. She says she had chemotherapy when she was first diagnosed in 2001, and "it took me a year to regain my strength."
When she started having intense back pains in 2004 and was told the cancer had come back in her bones, she was worried about the side effects of more chemo. She says with the low-dose approach, her cancer has remained stable and the main side effect has been fatigue. As part of her current regimen, she gets one of the same chemo drugs she took in the past, cyclophosphamide, but instead of 1,000 milligrams once every three weeks, she takes 50 milligrams every day. Compared with the higher doses she previously endured, she says, "this is a walk in the park."
Next Phase of Research
Harold J. Burstein, an oncologist at the Dana-Farber Cancer Institute who is the principal investigator of Ms. Fraley's trial, says he thinks the biggest benefits of anti-angiogenic chemotherapy will be in patients whose cancer isn't so advanced. He and researchers at Indiana University in Indianapolis have launched a pilot study open to women who got chemotherapy prior to surgery for breast cancer, but who had residual cancer in their breast or lymph nodes. These women are at high risk for recurrence, Dr. Burstein said.
Both this and his current trial are funded in part by grants from the National Cancer Institute and the Avon Foundation, as well as Avastin's maker, Genentech Inc.
"We need to generate more compelling clinical data if this approach is going to be useful," Dr. Burstein says.