It may seem cruel, but thwarting cancer sometimes requires subjecting the body to even more harm. When that body belongs to a child, victimized by some quirk of genetics, it seems both cruel and unjust. But for would-be healers working in a controlled research environment, the long road to a successful cancer treatment -- or cure -- usually consists of toxic baby steps, aided by some adult-size heroics from hospitalized kids. Sadly, when it comes to treating neuroblastoma, an aggressive and often fatal cancer that strikes mainly children, dire circumstances require daring therapy. And nowhere is this daring on better display than at UCSF Children's Hospital, where in a series of important clinical trials, a radioactive compound is being administered intravenously in doses so high that the neuroblastoma-stricken child is placed for days in a room surrounded by a lead shield.

"Children in clinical trials may not only be helping themselves, they're also helping many other children," says Kate Matthay, chief of pediatric oncology. "Clinical research has been the mainstay in advances in children's cancer." For more than 20 years, Matthay has treated scores of children with neuroblastoma and led clinical trials aimed at curbing the disease. She has seen kids die and families devastated. But she also has been invited to graduations, written letters of recommendation to medical schools, and followed former patients who now lead healthy and productive lives.

Neuroblastoma, which is diagnosed in some 650 US children each year, is a cancer rooted in the nerve cells of infants and very young children. Its cause is unknown, but scientists suspect that genetic events during embryonic development predispose a child. It is the most common solid tumor in children under one year and the third most common childhood cancer behind leukemia and brain tumors.

Neuroblastomas usually begin in the adrenal gland in the abdomen or in nerve tissue in the neck, chest or pelvis. Although they may be present at birth, they are often not detected until they have pushed their way to surrounding organs or metastasized to lymph nodes, bones, the central nervous system or bone marrow.

If the cancer has not moved beyond its original site, there is a great chance that surgery, radiation or chemotherapy -- or combinations of these -- can stifle the tumor. Unfortunately, in 60 percent of cases, the cancer has spread too far by the time it is diagnosed, says Matthay.

For those patients, treatment depends on the age of the child, the size and position of the tumor and how dangerously far the cancer has traveled. Matthay advises on neuroblastoma treatment strategy for the Children's Oncology Group, a national cooperative of pediatric cancer centers, and she is the principal investigator of a 14-university consortium -- New Approaches to Neuroblastoma Therapy (NANT) -- committed to working on clinical trials that will bring to the bedside the most promising treatments developed by researchers.

Matthay led a national team, which reported in 1999 that high-dose chemotherapy, irradiation, transplantation of the patient's own bone marrow cleansed of tumor cells, followed by treatment with a vitamin A-like drug called 13-cis-retinoic acid, tripled the likelihood that a child with advanced neuroblastoma would survive three and a half years. The research, which established a new treatment standard, has raised the chances of surviving metastatic neuroblastoma from 10 percent 15 years ago to about 40 percent today. But those figures are far from ideal, says Matthay. So, she and others -- at UCSF and around the country -- persist with more clinical trials in their quest to improve outcomes for the children battling this cancer.

One of the more intriguing and promising experimental treatments involves bombarding neuroblastoma tumors with a radioactive compound. Its roots go back to the late 1970s, when University of Michigan scientists attached radioactive iodine to a substance synthesized a decade earlier by chemists researching drugs for high blood pressure agents. The compound -- metaiodobenzylguanidine (MIBG) -- was being studied by the Michigan group as an imaging agent and later as a treatment for pheochromocytoma, a gland tumor. In 1982, scientists at UCSF extended the use of MIBG to imaging childhood neuroblastoma. MIBG was found to mimic a natural compound in the body that is concentrated in selective tissues, including neuroblastoma cells, and it binds to these tumor cells. By 1983, MIBG was being used routinely to diagnose and stage neuroblastomas. Infused into the patient, MIBG goes through the body and attaches to any neuroblastoma, and after the body is scanned, the tumors display starkly on X-ray-type images.

But at Michigan and UCSF, cancer fighters were determined to extend MIBG's use from "seek" to "seek and destroy." Combining MIBG with radioactive iodine (131-I) created a highly loaded radioactive weapon against neuroblastomas. "The drug fragments chromosomes in these cells to the point where they won't replicate," explains John Huberty, a radiopharmaceutical chemist in the Department of Nuclear Medicine. "You try to do this without causing irreparable damage to other tissue in the body."

It was Huberty in 1984 who proposed MIBG to pediatric oncologists, including Matthay, as an experimental therapy for children who were failing other neuroblastoma treatments. In 1986, Matthay first tested MIBG in a patient, and she has continually pushed for clinical research to improve the treatment for kids with the most advanced stages of the cancer. Since then, Huberty has personally prepared, in a delicate process that takes two-and-a-half days, every therapeutic MIBG infusion administered at UCSF.

Treatment usually starts with a regular low-dose MIBG imaging scan to pinpoint the tumors and ensure that the compound indeed targets and binds to the tumors. The therapeutic MIBG is later administered intravenously, and over two hours the tumors are flooded with radiation.

The treatment is not without discomfort. The young patients are considered "hot," or radioactive, and must be kept in a lead-lined room for as long as five days to protect parents, family members and hospital staff from radiation. Computers, which act as Geiger counters, measure the radiation levels in the room, and video monitors keep an eye on the child. A catheter is placed in the child's bladder to drain radioactive urine, and oral medications are administered to prevent thyroid damage from the radioactive iodine in the MIBG.

Kids can watch TV or play with toys and video games, but parents can usually have only 30 to 45 minutes of direct contact with their child in the first 24 hours. Although the length of time family can visit increases as radiation in the room decreases, the separation is often a hardship, considering that a youngster with such a difficult disease is often used to being cuddled for most hours of the day.

Some of the trials call for using MIBG with other treatments, including high-dose chemotherapy and bone marrow transplant. To date, some 170 kids with neuroblastoma have been treated with MIBG at UCSF, and in about one-third of the cases these difficult and recurrent tumors shrank by at least 50 percent, says Matthay. Sometimes, zapping away that much of a tumor leaves it vulnerable to other drugs, or it becomes easier to remove surgically. In a number of cases, MIBG has helped children survive the cancer for several years.

While there has been significant research and treatment progress over the years, MIBG therapy is nowhere near the lifesaver that its proponents need it to be. That will require more imaginative protocols -- and consequently more kids who are desperately seeking a way to eradicate the cancer.

One of Matthay's newer studies calls for boosting, even doubling, doses of radiation via MIBG to improve its anti-cancer effects. This is followed by infusing the child's own blood-forming stem cells, which are collected and stored beforehand, to "rescue" or regrow the blood cells that are killed by radiation and restore their immune systems. It is designed as a phase 1 study, aimed partly to learn what is the highest dose of radiation that the body can tolerate while destroying neuroblastoma tumors and still effectively regrow the blood cells. It may prove ideal for children with advanced neuroblastoma who are not yet too battered and worn out by the disease and other therapies.

Oftentimes, these trials offer the only hope for patients. Research cooperatives across the country, such as NANT, help match patients with the best-suited clinical trial.

Erin Whepley, of Wichita, Kansas, an eight-year-old whose intelligence and poise are beyond her years, was one of the first children enrolled in this newest trial. It was the beginning of last summer that her parents, Kathy and Brian, noticed the stiffness in her hips and back. By the end of August and after a string of doctor's visits and medical tests, they received the heartbreaking diagnosis of neuroblastoma. A very large tumor, lodged in a cavity between her pancreas and aorta, was in a spot too delicate and risky for surgery. Chemotherapy began right after Labor Day, but later tests would spot tumors elsewhere, including behind her neck.

In a way, they are lucky, says Kathy Whepley, a high school teacher. They had support and resources to quickly seek the best course of therapy for Erin. With physicians in their family and others to advise them, they connected with the top specialists in the country and researched all that was known about the disease and the potential treatments. Eventually a pediatric oncologist in Forth Worth, Texas, suggested the MIBG clinical trial at UCSF.

By the end of December, Janet Veatch, a UCSF clinical nurse specialist in pediatric oncology and a nurse coordinator for several clinical trials, was in touch with the Whepleys to explain the therapy. In January, they came to UCSF for their first visit with Matthay.

Consenting to a clinical study can be daunting. A 22-page form not only details every part of the procedure, but also warns of worst-case scenarios. One learns, for example, that common side effects include nausea and bone marrow suppression, and, in rare cases, sterility. Families are also told that blood cells are destroyed in the majority of patients who get this treatment, and this could be fatal if stem cell infusion rescue is not successful.

But with Erin's advanced stage of neuroblastoma, the Whepleys agreed that MIBG offered her a fighting chance of whipping the cancer.

In March, she began the treatment and a monthlong stay in and out of the Pediatric Clinical Research Center. There was the first infusion of the radioactive MIBG, the five-day stay in the special room and all the IVs, medications, tests and irritations that go in between. And then the process was repeated nine days later.

Erin received nearly 1,300 millicuries of radioactive MIBG over the two infusions. It's the highest amount of radiation to be administered in any of the UCSF trials of the therapy. "That amount of activity is indeed hazardous," says Huberty, who prepares the MIBG solution in a specially protected and equipped "hot cell" in the basement of the Medical Center. "What is absolutely essential is to design the treatment in a way that minimizes needless irradiation to normal tissues. This has been a very important part of the UCSF program."

On day 28 -- two weeks after the second MIBG treatment -- Erin received an infusion of her own stem cells. Later that day, she began another medication, delivered via IV over one hour and every day until enough white blood cells were present to fight possible infection.

Through it all, Erin handled it like a champ, impressing the hospital staff. Except for boredom from the isolation in the special room, the treatment is much easier for kids than chemotherapy, which can cause violent nausea, mouth sores and, of course, a loss of hair, says Veatch.

Erin returned to UCSF in early May for some follow-up tests. Results so far have shown a slight shrinkage of tumors from the MIBG. Some of the MIBG still sticks to tumors, so perhaps it is still doing its work. Initial bone marrow tests were clear, but later tests showed a very small number of tumor cells, said Kathy Whepley. In the meantime, Erin will be taking another drug, Fenretinide, a "biological response modifier" that is being tested on children with recurrent or resistant neuroblastoma. More protocols may be on the horizon.

The Whepleys perhaps have read the statistics about neuroblastoma, but they don't heed them. Erin is an individual case and a "sampling of one," says her mom. That is the way they must look at it. "We have hope, and we'll fight this," she says.

This is understood just by looking at Erin. She shows the battle signs of cancer -- marks from the many IV pokes and still some hair loss from the bouts of chemotherapy months ago -- but has a glimmer in her eyes.

"The children are the most remarkable participants in the whole thing," says Veatch. "Even if they've had bad luck, they still show hope. They are so resilient. They endure so much. Most adults would have thrown in the towel a long time ago."

Even from halfway across the country, Matthay and Veatch will follow Erin's progress closely. They take all their patients to heart. In the meantime, they will seek other kids with neuroblastoma who may be helped by one of their clinical studies. Perhaps they will do enough tests to find the optimal dosage and way to administer a therapy like MIBG. Maybe they will turn the odds in the kids' favor.

On the third floor nuclear medicine unit, three levels below the Pediatric Clinical Research Center, John Huberty often looks at the whole-body scan images of children with neuroblastoma. Sometimes he sees the dark blotches, indicating tumors riddled throughout the body. Other scans may show that a tumor has shrunk.

In the hallway outside are better images -- snapshots of former patients who are cheerleaders, teenagers or big brothers and sisters. They are pictures of hope.

See also:

Pediatric Clinical Research Center

UCSF Comprehensive Cancer Center