Diagnosing and Treating the Many Forms of Childhood Cancer and Blood Diseases

BY MARK SHWARTZ

WINTER 2001 - Lucile Packard Children's Hospital's world-renowned oncology and hematology program combines the most advanced clinical care with the latest scientific research. It is one of the few centers in Northern California to offer the broad range of expertise and innovative treatments for the variety of cancers and blood diseases that occur in children.

Leukemia

Leukemia, a disease of the white blood cells in bone marrow, is the most common pediatric cancer and accounts for about 31 percent of all cancers in children under age 15. Yet, the causes of childhood leukemia remain a mystery.

"We see between 25 to 40 children with newly diagnosed leukemia yearly at Packard," says pediatric oncologist Gary V. Dahl,M.D. "About 80 percent of the cases are acute lymphoblastic leukemia (ALL), the majority of which can be cured with chemotherapy. The remaining 20 percent are mostly kids with acute myeloid leukemia (AML), which is more difficult to treat."

Norman Lacayo, M.D., a Stanford researcher in pediatric hematology/oncology, has collaborated with Dahl in studies using micro array technology to analyze DNA and cell-surface markers in leukemia patients. The researchers are also using gene chip technology to explore and design multi-drug treatments that some day could inhibit the growth of leukemia cells.

"We now have a better understanding of leukemias at the cellular level," says Michael Link, M.D., Packard's chief of hematology and oncology. "All leukemias look the same under the microscope, but they aren't all the same disease," explains Link. "We use genetic analysis to determine the subtype of leukemia, because every patient is different."

For example, some children with ALL have too many chromosomes in their cells, while others have too few, and this influences the prognosis: Children with more chromosomes have a 20 percent to 30 percent better chance of survival than those with too few chromosomes. New efforts in research are creating even greater promise for future pediatric leukemia patients.

"In my career, I've seen cure rates for ALL go from 15 percent to 80 percent, and from 3 percent to 50 percent for AML," says Dahl. "If there are patients who aren't doing well, we can go back to the books and look for new drugs and treatments."

Brain Tumors

When neurologist Paul Fisher came to Packard in 1997, he knew he had found a home.

"There is no question that Packard is a top-tier hospital, and it treats more pediatric brain tumors than any other hospital in Northern California," says Fisher. "But what really sets it apart is that it's child-friendly. That's a Packard hallmark."

Prior to joining the Packard staff, Fisher ran the pediatric brain tumor division at Johns Hopkins University in Baltimore. For him, the difference between the two institutions is striking.

"When everything is geared for kids, it's very easy to do pediatric medicine," notes Fisher. "We can do things to fit our research and clinical needs. It's also an opportunity to work really close to families and patients."

Brain tumors are the second most common type of childhood cancer. Packard sees about 40 brain tumor patients each year -- almost 2 percent of the 2,200 pediatric brain tumors diagnosed each year in the United States.

Unlike many pediatric hospitals, Fisher says, Packard offers both a solid clinical research program and a multidisciplinary array of services, including neurosurgery, neurology, oncology, pathology, radiology, physical therapy, nursing, psychology, and a program to deal with learning difficulties. He also acknowledges Packard's special events, such as a recent picnic for brain tumor patients and survivors that brought together some 50 families and Hospital staff.

Neurologists have identified about a dozen different types of brain tumors, from astrocytomas, the most common form, to the relatively rare germinoma [see Bradley's story]. Although each type has its own treatment regimen, 80 percent of all brain tumors require surgery, 60 percent require radiation, and 40 percent require chemotherapy.

The overall five-year survival rate for brain tumors is about 60 percent, depending on the type. "Cerebellar astrocytomas have a 95 percent survival rate," observes Fisher, "but when it comes to kids with brain stem gliomas, it's still a challenge -- only 1 in 100 survive."

"Our job is not only to cure but to care," concludes Fisher. "You go into it knowing you're not going to win every time, but if you keep showing up, you never know what will happen."

Radiation Oncology

Radiation is one of the most common treatments for children with cancer.

"Today we have new ways of using 3-D conformal therapy to target the disease while doing minimal harm to the patient," says Sarah S. Donaldson, M.D., chief of radiation oncology at Packard.

She points out that Stanford pioneered the practice of combining chemotherapy and low-dosage radiation for children. "The first clinical trial began in 1969, and since then we've refined our technique to use lower doses of radiation to cure the largest number of children with the least side effects," notes Donaldson.

She adds, "Collaboration is the key to bringing about a higher cure rate, because many children with cancer need some combination of surgery, chemotherapy, and radiation. One treatment isn't more important than another."

All radiation -- pediatric and adult -- is performed at Stanford Hospital's state-of-the-art facility, but young children require special attention. "Radiation therapy involves directing a radioactive beam at a localized target, so the patient has to remain perfectly still," explains Donaldson. "Older children usually cooperate, but younger ones have lower attention spans and tend to wiggle. Therefore, we must use special immobilization techniques that are complex." Infants usually are anesthetized -- a procedure that requires the expertise of Packard's pediatric anesthesiologists.

"There's so much talent at Stanford -- brilliant minds, gifted researchers," says Donaldson, "plus we are in the heart of Silicon Valley where we've had an explosion of technological advances, so in many respects Stanford and Packard are always several steps ahead of other academic centers."

Hematopoietic Stem Cell Transplants

About 35 children receive hematopoietic stem cell transplants at Packard Hospital each year. "Hematopoietic" refers to stem cells that give rise to mature blood cells. Hematopoietic stem cell transplants are designed to replenish these stem cells, which may be destroyed by chemotherapy and radiation, or may be damaged by some other disease process. The most common source of stem cells is bone marrow, but cells also can be harvested from peripheral blood and placental and umbilical cord blood.

"Bone marrow transplants are now a standard treatment for many pediatric illnesses, including leukemias and lymphomas, as well as other, non-malignant conditions such as aplastic anemia and thalassemia," says Michael Amylon,M.D., director of Packard's Bone Marrow Transplant Service.

"There aren't many places in Northern California that do pediatric transplants," adds Amylon, whose transplantation team includes specially trained physicians, nurses, therapists, and nutritionists.

Children who undergo the procedure usually require six to 10 days of pre-transplant conditioning with radiation and chemotherapy. Side effects -- such as organ damage, blood-count drop, hair loss, and mouth lesions -- can occur within two weeks. After the transplant, children may have to stay in isolation for up to 30 days -- an expensive procedure often requiring families to spend a great deal of time away from home.

Bone marrow transplants have a 5 percent to 10 percent mortality rate -- a risky procedure for the recipient, though not for the donor. To minimize the chance of donor rejection, Packard also performs autologous transplants in which the child's own bone marrow is harvested and stored for later infusion.

"We're also looking to new technologies," adds Amylon. Among them: nonmyeloablation transplantation -- a less intense therapy designed to reduce side effects by retaining some of the patient's bone marrow or peripheral blood.

"Unlike traditional bone marrow transplants, non-myeloablative transplants are outpatient procedures," explains Amylon. "Packard was among the first to put this technique into clinical trials, and we plan to continue being on the cutting edge of novel therapies."

Blood Diseases

Packard's hematology program provides treatments for several different types of non-malignant blood diseases, including hemophilia A and B, inherited diseases that prevent normal blood clotting; aplastic anemia, a severe bone marrow disorder; and hereditary anemias, such as sickle cell disease and thalassemia, a genetic disorder that affects hemoglobin production and is most commonly found in Mediterranean and Near Eastern populations.

Packard sees more than 150 hemophiliac children and young adults each year. "Children with severe hemophilia frequently died or developed severe, crippling orthopedic deformities due to bleeding in their joints until new treatments came along in the 1960s," says Bertil E. Glader, M.D., Ph.D., professor of pediatrics in Stanford's Oncology and Hematology Department. "The first therapy for severe hemophilia was actually developed here at Stanford," he notes.

In addition to the specialized clinical care, Stanford also is leading research efforts in hemophilia. Glader and Stanford colleague Mark Kay, M.D., Ph.D., are working with colleagues at the University of Pennsylvania to conduct an innovative gene therapy trial to treat hemophilia B, a form of the disease in which patients have low levels of a protein called clotting factor IX.

"We use a safe virus to insert the factor IX gene into the liver. The hope is that the gene will be expressed and thereby produce a protein that promotes clotting," explains Glader. "It's very preliminary, but very exciting. If this gene therapy proves successful, it will have ramifications in other diseases."

Sickle cell disease -- another inherited illness -- results in malformed hemoglobin molecules, which clump together inside blood vessels causing episodes of extreme pain.

"Some kids with sickle cell have strokes by age three," observes Glader. "Ten percent might have a stroke before adulthood. By age 20, we see failure of many other organs that shorten life expectancy to around age 45."

Aplastic anemias occur when the bone marrow is unable to manufacture enough blood cells. The cause sometimes is environmental, a result of exposure to toxic pesticides or radiation; a number of cases occurred after the Chernobyl nuclear accident in the former U.S.S.R. Children with leukemia also can acquire aplastic anemia following radiation therapy.

"We have made progress," Glader concludes. "With aplastic anemia, kids are living longer now. With thalassemia, most died in their teens, but now they're living into their 20s and 30s.With sickle cell, infections used to be the major cause of death in childhood, but now that's markedly diminished with new treatments, thanks in large measure to clinical trials. And with hemophilia, new therapies made with recombinant DNA technology are safe and effective, and we hope will allow children with hemophilia to have a normal life expectancy. So things are changing right in front of our eyes."

Lymphomas

Lymphomas -- malignancies of the lymphoid cells -- are the third most common type of cancer in children, accounting for about 15 percent of childhood cancers.

The two main types of lymphomas, based on their microscopic appearance, are Hodgkin disease and non-Hodgkin lymphoma (NHL), which is the most common type of lymphoma in young children. Although the two diseases are distinct, both often present with swelling of the lymph nodes in the neck and chest.

"The cure rate for pediatric Hodgkin disease is now more than 90 percent, thanks in large part to the successful combination of chemotherapy and radiation pioneered at Stanford in the 1970s," says Sarah S. Donaldson, M.D.

The overall survival rate among children with NHL also has shown a dramatic turnaround, improving from 56 percent between 1975 and 1984 to 72 percent in 1994.

"For kids with the early-stage form of NHL, survival now exceeds 90 percent," notes Packard oncologist Michael P. Link, M.D. "It's a pediatric oncology success story."

Donaldson points out that Packard remains a leader in developing safer, more effective therapies for children with Hodgkin disease. She and Link conducted a study in 1997 which showed that the standard chemotherapy regimen term could be reduced by more than twothirds, or from eight months to 9 weeks. Another study demonstrated that radiation was unnecessary in children diagnosed with early-stage NHL.

"Our overall philosophy is to cure with less toxicity and without side effects," adds Donaldson.

Neuroblastoma

Neuroblastoma is a solid tumor that often begins in the adrenal gland and spreads to the bones, lymph nodes, liver, and other organs. The cancer is commonly seen in toddlers and children under 5, but also occurs in newborns and

"We see between five and 10 children with neuroblastoma at Packard each year," says pediatric oncologist Clare J. Twist, M.D. "The troubling thing is that, by the time it's diagnosed, it usually has already spread throughout the body."

Children with advanced neuroblastoma often have bone pain -- an indication that the disease has metastasized. Because the cancer is so aggressive, only about 30 to 40 percent of patients with the metastatic form of the disease survive. Infants have a greater chance of survival, though the reason is unknown. The usual treatment involves surgery to remove the tumors and several months of chemotherapy, but Twist and her colleagues have moved well beyond the standard approach.

"We are trying to develop novel therapies for those with a poor prognosis," notes Twist. "Unfortunately, that's the majority of our patients."

Recent studies have shown that a treatment regimen, which includes an initial phase of chemotherapy, followed by surgery, radiation therapy, autologous stem cell transplants, and large doses of a vitamin A derivative doubles the likelihood of a patient's survival without the recurrence of this high-risk disease.

Packard also is participating in a 10-institution study of neuroblastoma patients who do not respond to aggressive traditional therapy. This study utilizes the radioactive compound 131I-MIBG (iodine-131-meta-iodobenzyl guanidine) which is actively taken up by neuroblastoma cells and therefore provides a way of delivering targeted radiation to the tumor.

"Packard is now in a position where we can offer almost every new therapy available to fight this disease," says Twist. "We're continuing to learn more about the biology of this tumor to a much greater degree than other pediatric solid tumors. As a result, neuroblastoma is actually leading the way for other pediatric cancer biology research.