ADHEREX IN WALL STR. JOURNALEfforts Mount to Make
Cancer Treatment Less Toxic
New Drugs Aim to Reduce
Side Effects of Chemotherapy;
Protecting a Child's Hearing
By AMY DOCKSER MARCUS
Staff Reporter of THE WALL STREET JOURNAL
July 14, 2004; Page D1
As the number of long-term cancer survivors continues to increase, doctors are starting to focus attention on another issue: how to make cancer treatments less toxic without diminishing their effectiveness.
The growing effort to reduce or eliminate the side effects of radiation and chemotherapy has enormous implications for patients. Some researchers argue that if therapy becomes less toxic, it will make possible more-aggressive treatments that can push survival rates up further. The five-year survival rate for people diagnosed with cancer is now 64%, up from 59% in the early 1990s, according to a recent report by the National Cancer Institute and the Centers for Disease Control and Prevention.
Cancer treatments are known to cause a range of long-term health problems for survivors, including hearing loss, heart damage, joint problems and memory problems. Indeed, a study in last week's New England Journal of Medicine provided startling evidence of the extent of heart damage experienced by childhood cancer survivors.
The drive to "detoxify" has always played some role in treatment decisions. Most patients today receive what is called combination therapy; the hope is that using a careful mix of surgery, chemotherapy, radiation and a variety of drugs -- rather than one single powerful agent -- will reduce the overall toxicity of treatment. But "we've gone about as far as we can with this in most regimens," says Archie Bleyer, professor of pediatrics at M.D. Anderson Cancer Center in Houston.
Now, in the push to detoxify further, doctors are focusing on new drugs that can be added to chemotherapy regimens specifically to protect particular organs against side effects, including problems that won't show up for years. A variety of clinical trials are under way or about to start testing drugs designed to protect against heart damage and hearing loss -- two particularly pervasive problems.
The Children's Oncology Group, a consortium of institutions that treat pediatric cancer, is trying to determine if changing the dosing or type of various steroids used in cancer regimens can maintain high survival rates and prevent severe, debilitating joint damage in adolescents. To preserve fertility, some top cancer centers are surgically moving a woman's ovary out of the line of radiation or substituting chemotherapy agents considered less detrimental to sperm production. There is even some promising data that women's breaths can be synchronized with the radiation beams during breast-cancer treatment to help minimize damage to the heart.
"It is not enough to look at curing cancer," says Julia H. Rowland, director of the Office of Cancer Survivorship at the National Cancer Institute, which is putting more money into this kind of research. "We have to return people to a normal life."
The biggest obstacle to these efforts is ensuring that the drugs minimize damage to organs but don't interfere with chemotherapy's effectiveness in killing tumors. Plus the protective methods may have side effects of their own. At least one study of Hodgkin's patients showed that those who received a drug being studied as a possible protective agent as part of their cancer therapy had an increased risk of second cancers.
The hope of preserving a normal life for their son was a key part of the efforts of Billie and Shane Reagan, who live in DeKalb, Mo., as they sought treatment for their son Zane. Diagnosed at the age of 10 months with a brain tumor, he underwent two surgeries, a bone-marrow transplant and chemotherapy that included the drug cisplatin. Cisplatin and other platinum-based therapies can cause hearing problems by damaging the hair cells, a type of nerve cell, of the inner ear. Almost immediately after starting chemo, Mrs. Reagan says, tests showed Zane had suffered high-frequency hearing loss, a common side effect of cisplatin.
When the cancer came back two years ago, the couple took Zane to the Oregon Health & Science University in Portland, Ore., where doctors suggested adding another drug, sodium thiosulfate, to the chemotherapy to prevent his hearing from deteriorating further.
Each time Zane received chemotherapy, he was given sodium thiosulfate twice, once four hours after treatment and then again eight hours after treatment. Today, at the age of 5, his hearing loss remains stable and there is no sign of tumor recurrence. He uses hearing aids, but has normal speech and will enter a regular kindergarten class in the fall.
The Children's Oncology Group plans to start a clinical trial later this year evaluating the efficacy of sodium thiosulfate in preventing hearing loss. Edward Neuwelt, Zane's doctor at Oregon Health, says his team has also presented research indicating the drug prevents against the loss of platelets, another common side effect of cancer treatments that can inhibit the blood's ability to clot, leading to hemorrhages. He has opened a clinical trial to test this further.
Adherex Technologies Inc., a Canadian company with its headquarters in Research Triangle Park, N.C., is developing sodium thiosulfate to protect against hearing loss in children receiving cisplatin, and also hopes to develop the drug for use in adult head and neck cancer, where intensive platinum-based therapies are used and irreversible hearing loss is common. Many of the studies in this area have focused on children because they were the first group of patients to survive in large enough numbers and for a long enough time that long-term health effects turned up.
The study in the New England Journal of Medicine last week showed promising results from the use of a drug called dexrazoxane to protect against heart damage in children with acute lymphoblastic leukemia, the most common form of childhood cancer. There are now more than 250,000 childhood-cancer survivors living in the U.S., according to the study. It is estimated that more than half of these 250,000 were treated with the chemo drug doxorubicin or some similar agent as part of their chemotherapy. One of the side effects of doxorubicin is an increased risk of sudden death or death from cardiac causes and heart failure -- a risk that can continue for many years after cancer treatment ends.
In the study, children treated for acute lymphoblastic leukemia, or ALL, with doxorubicin alone were more likely to show elevated levels in their blood of a protein -- indicating heart-cell injury -- than children who got dexrazoxane. Both groups of children experienced an 83% survival rate.
The children in the trial will continue to be monitored to see if there is any change over time in heart function or in the survival rates of the two groups. Much still isn't known: Oncologists are uncertain about the optimal dose of the protective agent. Giving protective drugs too close to the time of chemotherapy might impact the chemotherapy's effectiveness; waiting too long afterward might diminish the protective agent's ability to work.
But Stephen E. Sallan, chief of staff at the Dana-Farber Cancer Institute in Boston and a senior author of the study, says all children treated for ALL at Dana-Farber now receive dexrazoxane as part of their treatment to protect against heart damage. The next step, he says, is to test it in other diseases that also use doxorubicin as part of the chemotherapy.
A key concern remains maintaining survival rates. "You can't risk efficacy," Dr. Sallan says.
Still, for Billie Reagan, Zane's mother, the new approach has already made a difference. "We would have let Zane's hearing go to save his life," she says. "But if there was any way to prevent something that would be a hardship to him later in his life, we wanted to do it."