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Radioactive Compound Impacts Neuroblastoma

RADIOACTIVE COMPOUND USED FOR IMAGING NEUROBLASTOMA MAY HELP KILL IT, TOO

originally posted December 5, 2000

ANN ARBOR, Mich. - A radioactive compound used for the past two decades to find certain types of cancer is now showing surprising promise in helping to kill those tumors too, according to new results from a small trial at the University of Michigan Comprehensive Cancer Center.

All 11 children treated for neuroblastoma in the drug's first clinical test initially had a positive response with no significant side effects, lead researcher Gregory Yanik, M.D., will report in an oral presentation on Dec. 5 at the annual meeting of the American Society of Hematology in San Francisco.

The compound, called MIBG, was originally developed and patented at the U-M in the 1970s and is now used around the world in medical imaging to find and classify certain forms of cancer -- including neuroblastoma, the second most common solid childhood cancer. New results indicate that higher doses of MIBG can also help shrink the same tumors.

"MIBG can act as a tumor bullet, specifically targeting the neuroblastoma itself, sparing other parts of the body from complications or side effects," says Yanik. "Because of this, we hope that with further research MIBG will ultimately help treat and perhaps cure many patients with neuroblastoma."

Yanik, a clinical assistant professor of pediatrics and a bone marrow transplant specialist, leads the U-M team that incorporated MIBG into a neuroblastoma treatment regimen, combining it with chemotherapy and a transplant of the child's own bone marrow. In the Phase I trial, the therapy produced partial remission in three children and complete remission in eight others. All were aged 2 to 14 years and had a history of advanced, or persistent, neuroblastoma.

The MIBG regimen caused many of the patients' tumors to shrink or disappear entirely for at least 100 days - and up to one year - with few side effects. But, Yanik cautions, "It's still too early to tell if it will be long-lasting." Some have since relapsed and died, while others continue to be stable. Neuroblastoma accounts for 8 percent of all childhood cancers, arising in about 500 children each year in the U.S.

Neuroblastomas are typically diagnosed in the first few years of life. The disease may start in developing cells in the adrenal glands or lymph nodes in the abdomen or chest. It spreads quickly, and more than half of all patients aren't diagnosed until satellite tumors have developed in the bone marrow or bone. Its cause is unknown, but experts suspect it may come from a genetic event during prenatal development that predisposes a child to the disease.

More than 60 percent of all neuroblastoma patients have an advanced stage, high-risk form of the disease that is often resistant to treatment.

Advanced-stage patients usually have a life expectancy of one to two years; many of the patients in the U-M trial had a worse prognosis because they had failed prior treatment. Advanced neuroblastoma patients often undergo surgery along with radiation therapy and chemotherapy, and may even have a transplant of their own bone marrow.

"Despite all the modern advances we have in medical science, still only 25 to 30 percent of children with advanced neuroblastoma are able to be cured at this point in time," Yanik says. "One of the thoughts is that we're still not achieving optimal delivery of the therapy to the tumor itself."

That's why the idea of using MIBG is so promising, Yanik explains. The compound combines a substance called meta-iodobenzylguanadine -- similar to norepinephrine -- with a radioactive form of iodine called iodine-131. It was originally developed at the U-M to treat high blood pressure, but researchers discovered another effect: the MIBG was found to bind to tumor cells that produced chemicals called catecholamines - for instance, neuroblastomas.

"MIBG will go through the body looking for that neuroblastoma, and once it finds it, it will bind to it," Yanik explains. "That finding led the University of Michigan to pioneer the use of MIBG in the 1970s and 80s to diagnose neuroblastomas. The MIBG is given as an infusion into a patient's IV, and attaches to any neuroblastoma that's in the body so that we can see it on an X-ray type image."

Ninety percent of neuroblastomas will take up the MIBG. If, however, the MIBG can't successfully attach to a patient's tumor, it can't be used to find or treat it.

Prior trials at the U-M and elsewhere attempted to use MIBG alone. But, says Yanik, "At the U-M, we determined that if we combined bone marrow transplant with MIBG therapy as two knock-out punches back to back, we might have success in treating patients with extensive neuroblastomas."

The protocol used to produce the new results was developed through cooperation among U-M nuclear medicine specialists, oncologists, radiologists and bone marrow transplant specialists. The MIBG is made at the Phoenix Memorial Laboratory, the U-M nuclear research laboratory.

The regimen starts with a regular low-dose MIBG imaging scan, to make sure the patient's tumors will take up the compound and to pinpoint where the tumors are found. Then, the U-M team harvests and freezes some of the patient's bone marrow, before starting a 21-day attack.

The assault on the cancer starts with an infusion of the MIBG solution in the patient's IV. The MIBG is administered over 90 minutes to the patient in a special lead-lined hospital room. The shielding around the patient keeps parents and other healthy people from exposure to radiation.

During the three to five days in the special room, the children can watch TV and play with video games or toys while the radioactivity in the MIBG does its silent work attacking the tumors. Though the dose is high, the only side effects reported during administration of the MIBG were mild nausea and vomiting.

Three to four days after receiving the MIBG, patients are discharged from the hospital. They are then re-admitted in two weeks for four days of high-dose chemotherapy followed by an infusion of their stored bone marrow. The patients are then required to stay in the hospital for several weeks to recover from the transplant.

The promising results from the initial U-M trial have led to the research being performed in several other pediatric transplant centers in the U.S. The U-M has joined forces with several other medical centers, including the University of California at San Francisco, Children's Hospital of Los Angeles, and the Children's Hospital of Philadelphia, to treat patients with MIBG using a common protocol.

Meanwhile, Yanik and his colleagues continue to perform research designed to help predict which patients may benefit most from MIBG earlier in their treatment course, rather than waiting until they have failed conventional treatment.

Facts about neuroblastoma and MIBG:

  • Neuroblastoma is the second most common form of solid tumor in children, and accounts for 8 percent of all childhood cancers.
  • Patients with stage I and II neuroblastoma have over a 90 percent survival rate. Those with stage III have over a 60 percent survival rate, but those with stage IV disease have only a 25 percent chance of five-year survival with modern therapy. The survival rate drops to less than 10 percent if patients fail to respond to chemotherapy or relapse.
  • By the time 50 to 70 percent of neuroblastomas are initially found, they've metastasized (called stage IV disease.) ยท MIBG was developed and patented by the U-M in the 1970s. In the 1980s a technique was developed using MIBG to find neuroblastomas and other similar type tumors.
  • MIBG is now made commercially for medical imaging, and helps find hundreds of neuroblastomas a year. But only the U-M and the University of California at San Francisco make it for therapeutic purposes.

Find out more on the Internet at: U-M Comprehensive Cancer Center:

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