The vast majority of patients with Hodgkin's lymphoma (HL) can be cured, but some go on to develop another cancer or heart disease later in life. Many patients are young, and the risks of secondary illnesses caused by curing the disease are increasingly viewed as unacceptable. The challenge for the field now is to develop less toxic therapies that still cure patients.

"HL is facing the same issues as any other disease or any other cancer," said Dr. C. Norman Coleman, who directs NCI's Radiation Oncology Sciences Program. "Basically you'd like to be able to predict who's going to respond to which therapies, and begin to select individualized therapies."

A disease of the lymph system, HL was one of the first cancers found to respond to radiation and also one of the first success stories of chemotherapy. Most patients today are treated with chemotherapy and radiation, but there is no consensus among the experts about which combinations work for which patients, or even whether radiation should routinely be given along with chemotherapy.

Clinical trials are under way around the world to try to resolve some of these long-standing questions. Meanwhile, researchers are trying to identify genes, proteins, or other biological markers associated with a patient's response to treatment. If doctors could identify responders and nonresponders, they could begin to tailor therapies to individual patients.

In Germany, for example, a pilot study is under way to create a "toxicity index" that doctors might use to make decisions about treatments based on a patient's genetic makeup. To create the index, researchers will catalogue more than 800 patients, noting variations in the genes involved in breaking down drugs. These volunteer patients will be followed for at least 5 years.

One of the first clinical applications of such an index might be to identify patients at risk for severe toxicity who should, therefore, be treated in a hospital rather than on an outpatient basis, as is typically done.

"Many patients prone to developing toxicity from cancer treatment would have a better clinical outcome if treated as inpatients, but this requires that you identify these patients first," explained Dr. Roman Thomas of the University Hospital of Cologne, Germany, who is leading the index project and is currently at the Dana-Farber Cancer Institute.

Perhaps the most effective way to deal with the toxicity problem would be to develop targeted therapies along the lines of a drug like imatinib (Gleevec) that selectively kills cancer while sparing healthy tissues. In recent years research on the cells involved in HL has suggested several avenues of research, but the key events that cause cells to become malignant are not yet known.

"Much progress has been made, but we still don't know the primary transforming mechanisms in HL, and these are likely to provide the good drug targets," said Dr. Daniel Re, a member of the German Hodgkin's Lymphoma Study Group (GHSG) who is currently at the Burnham Institute.

GHSG leaders are planning to form a new HL study group this June at a scientific meeting in Lugano, Switzerland. "The aim is build a registry for all ongoing studies and to recruit more patients for early clinical trials dealing mostly with experimental therapies in a shorter time," explained Dr. Re.

HL is relatively rare and develops slowly so it can take a long time to gather meaningful results about the effectiveness of new therapies. In addition, the ability to cure 90 percent of patients has made many doctors understandably cautious about new therapies and less likely to enroll patients in experimental trials.

"When you are so successful in treating a disease it becomes harder to back off and try new approaches," said Dr. Vincent DeVita, Jr., of Yale University's Cancer Center. In an editorial published in the January issue of Nature Clinical Practice Oncology, he calls this reluctance to explore experimental therapies "the curse of the cure."

But he has reason to be hopeful. HL faced a similar situation in 1964, when studies led by NCI demonstrated that chemotherapy drugs were more effective than the then-current practice of radiation. These new chemotherapy treatments, which were eventually adopted, are still used today.

"The good news is that 30 years ago people used to die of this disease, and now they don't," said Dr. DeVita.

By Edward R. Winstead