MCW Researcher Studies Role of Gallium as Anti-Cancer Agent

As part of the immune system, lymph nodes throughout the body create and filter the flow of lymph, which contains infection-fighting white blood cells called lymphocytes. In adult non-Hodgkin's lymphoma, malignant cells form in the lymph system, disrupting the lymphatic process and causing devastating illness and often death.

Research with the drug gallium nitrate shows promise in treating patients with low- to intermediate-grade non-Hodgkin's lymphoma (NHL), according to Christopher R. Chitambar, MD, Medical College of Wisconsin Professor of Medicine (Neoplastic Diseases and Related Disorders).

Dr. Chitambar has served as principal investigator for several studies of the role of gallium compounds as anti-cancer agents. Results from a Medical College study indicated that gallium nitrate produced shrinkage of lymphoma tumors in 6 out of 14 patients whose disease had relapsed after conventional treatment; in two patients there was almost complete disappearance of the lymphoma tumors for variable periods of time.

Although no patients were cured of their lymphoma, patients who responded to the gallium treatment had relief of symptoms. That level of "palliation," or improvement in symptoms, and the unique properties of gallium in chemotherapy - it seems to target lymphoma cells while not suppressing bone marrow - have led to further study and the clinical use of gallium nitrate in many NHL patients.

"Gallium nitrate is active in lymphoma, and there's a history behind this," said Dr. Chitambar, a national leader in gallium research. "It's a drug that's been approved by the Food and Drug Administration for hypercalcemia (an excess of calcium in the blood), but there's a body of data that shows it also works in lymphoma in some patients.

"My research has been to try and determine why gallium nitrate works in some patients and not in others. There's a lot of basic laboratory research involved; we're trying to understand its mechanisms and its cellular protein targets. Maybe 'Patient A' will respond because his or her lymphoma has a certain protein. We're working on identifying these proteins, but that work is still in a pre-clinical phase."

"Lymphoma and bladder cancers seem to be the two diseases that are sensitive to gallium," explains Dr. Chitambar, "primarily because they have receptors that 'take up' the gallium nitrate. We think that's one of the mechanisms by which gallium nitrate kills lymphoma cells.

"Gallium nitrate is a drug that does not cause a suppression of the white blood cells; this suppression is a major drawback with many chemotherapy drugs. In fact, patients may reach a point where you cannot give them other chemotherapy drugs because they have developed low blood counts from all the treatment they have previously received and cannot tolerate a further decrease in their blood counts. Gallium nitrate tends not to do that."

Incidence on the Rise
The incidence of non-Hodgkin's lymphoma in the US has risen progressively since 1970, Dr. Chitambar said, but the reasons for the increase are not known. For the year 2003 an estimated that more than 53,000 new cases were identified nationwide, including about 1,200 new cases in Wisconsin and 540 NHL-related deaths.

More use of increasingly successful bone marrow transplantation to treat lymphoma, along with advances in multi-agent chemotherapy, have greatly reduced the death rate since 1970, when almost every case of lymphoma was fatal. Therefore, the role of gallium compounds as a tool for treatment, including palliation, may grow in importance as NHL patients live longer.

"Right now, if we're going to go forward and use gallium nitrate in patients, we would use it in patients who cannot be treated with other means, especially if they have low blood counts that make it impossible to use conventional chemotherapy," said Dr. Chitambar. "The drug is available to any physician who wants to use it, but since it is FDA-approved for treatment of hypercalcemia and not yet for lymphoma, its use in this setting would be considered off-label use."

Dr. Chitambar is presently serving as Principal Investigator for the Medical College in a national study sponsored by the manufacturer of gallium nitrate (Ganite) to evaluate therapeutic patient response to the compound, as well as its impact on their quality of life. Nationwide, eighty patients were included in this study, divided into two equal groups receiving different doses of Ganite. The study focused on patients who had relapsed or failed to respond to conventional chemotherapy treatment; the final data are not yet available.

Bone Marrow/Stem Cell Transplant Issues
Dr. Chitambar said that gallium nitrate could play a role in the treatment of patients who are not candidates for bone marrow transplant or have had their lymphoma recur after a transplant.

"If a patient had relapsed lymphoma that was shrinking and if this patient was a candidate for bone marrow transplantation, that would be a reasonable option for cure," said Dr. Chitambar. "On the other hand, if their disease was not shrinking with conventional chemotherapy, or if they were too old or had other issues that precluded the use of transplant, we would then consider treating them with something like gallium nitrate.

"The Medical College has been at the forefront of this work. I've been here twenty years, conducting gallium research, trying to understand why and how it kills cancer cells. We did a study several years ago (published in the American Journal of Clinical Oncology, Vol. 20, April 1997) that confirmed results from earlier studies showing that 43% of patients with recurrent lymphoma who were treated with gallium nitrate had shrinkage of their tumors.

"When used alone, it's not a cure, but it's a good form of palliation and that really makes a difference in quality of life. In the future, we intend to combine gallium nitrate with other chemotherapeutic drugs in the hope that this will improve the results of treatment and increase the cure rate in this disease."

Dan Ullrich
HealthLink Contributing Writer

MCW Health News presents up-to-date information on patient care and medical research by the physicians of the Medical College of Wisconsin.