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José Meléndez comes from a tropical island; Emily Miller from a bustling college campus. Like scores of others before them, these patients have come to St. Jude Children’s Research Hospital to beat osteosarcoma, the most common type of bone cancer in children.
Patients with this disease are usually adolescents or young adults, with tumors in their legs or arms. At St. Jude, physicians and scientists are teaming up to boost survival rates for this disease while reducing treatment side effects.
José and Emily took part in the OS99 protocol at St. Jude. This treatment plan consists of intensive chemotherapy, followed by an operation to remove the tumor and then more chemotherapy to kill any surviving cancer cells.
OS99 differs from other treatment plans in the world because it uses a drug called carboplatin along with ifosfamide and doxorubicin. Carboplatin is easier on the kidneys and the hearing than drugs that have been used in past osteosarcoma treatment plans. The protocol also avoids high-dose methotrexate, which can harm the kidneys, liver and lungs.
Because it is located in a bone, an osteosarcoma does not shrink like a soft-tissue tumor would. Clinicians have only one reliable way to find out how well chemotherapy has killed cells—by looking at the tumor under the microscope after the cancer has been surgically removed. But St. Jude is using a new way to evaluate treatment response. Dynamic enhanced magnetic resonance imaging (DEMRI) is a special kind of MRI in which radiologists inject a contrast solution to help them examine the tumor.
“We are one of the pioneers in this type of research,” says Najat Daw, MD, of St. Jude Hematology-Oncology. “DEMRI can be used to assess the blood supply to the tumor. That information may help us improve therapy for osteosarcoma.”
The protocol benefits children far from Memphis, Tennessee. “The exciting thing about this study is that it’s the first therapeutic protocol at St. Jude to be done in collaboration with an international partner site,” Daw says. Nine patients in Chile are currently taking part in the study. Physicians in that country have regular videoconferences with St. Jude faculty to discuss treatment progress and other issues.
Years ago, the only way to remove osteosarcoma was to amputate the affected limb. As survival rates increased, doctors sought ways to remove the cancer while improving patients’ quality of life. Today, St. Jude surgeons perform about 23 limb-salvage operations a year. In these surgeries, they replace diseased bones with prostheses. If a patient—such as Emily—has reached maturity, doctors anchor a super-strong “bone” made of cobalt and titanium to the patient’s existing healthy bone. But if a child—such as José—is still growing, surgeons use an expandable prosthesis, called Repiphysis® Expandable Implant.
In the past, surgeons operated on young patients each time they had a growth spurt. Although some prostheses were expandable, children had to undergo surgery for the expansion to occur.
“If kids had the potential to grow four or five inches, we’d have to operate on those kids four times,” recalls surgeon Bhaskar Rao, MD. “Then you had the risk of infection and bleeding, plus you had to start all over again with weeks of rehabilitation.”
With the new prosthesis, a donut-shaped coil emitting an electromagnetic field is held around the child’s limb. This magnetic field heats a plastic tube within the prosthesis. As part of the tube melts, an internal spring uncoils and the prosthesis lengthens. In the late 1990s, Rao and his colleague Michael Neel, MD, began using Repiphysis® at St. Jude. To date, they have implanted 36 of the devices. Rao has even traveled to a St. Jude partner site in Lebanon to teach surgeons how to perform the operations. St. Jude physicians are also investigating whether they can reduce the amount of normal bone that is removed during surgery, so that children can keep more of their natural bone when prostheses are implanted.
If the osteosarcoma has not spread, children with the disease have about a 75 percent chance of survival, compared with about 20 percent in the early 1960s. Treatment has not changed much in the past 15 years, mostly because this kind of cancer is not very sensitive to chemotherapy. The laboratory may hold the answer to better cure rates.
A recent discovery by a team led by Jeffrey Dome, MD, of Hematology-Oncology has moved investigators one step closer to identifying patients who are at higher risk of death or tumor recurrence. By looking at osteosarcoma tumor samples from 51 children, Dome and postdoctoral fellow Robert Sanders, MD, found that patients whose tumors express the telomerase gene are at higher risk of having a bad outcome than children whose tumors do not express the gene.
Telomeres are DNA sequences that cap the ends of chromosomes. In normal cells, telomeres serve as a kind of molecular clock. Telomeres shorten each time cells divide, eventually becoming so short that the cell knows it’s time to stop dividing. In cancer cells, an enzyme called telomerase maintains telomere length, and the cell continues to divide with abandon.
Although most cancers express telomerase, many osteosarcomas do not; most of them use a process called “alternative lengthening of telomeres” (ALT) to maintain telomere length. “We found that when these tumors do have telomerase, they are harder to cure,” Dome says. This finding appears in the September 2004 edition of the Journal of Clinical Oncology. Results of the study could help physicians identify ways to modify therapies and increase survival rates for kids whose tumors express telomerase.
“I’m excited about all of these collaborations,” Daw says. “By studying the biology of this disease, we will be able to understand what causes osteosarcoma, the tumor’s characteristics and how we can treat it better.”
Reprinted from winter 2005 Promise magazine
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