Radioimmunotherapy Faces Obstacles as Lymphoma Treatment

Proponents of radioimmunotherapy (RIT) for people with non-Hodgkin lymphoma (NHL) say FDA restrictions, differences among medical subspecialties, professional conservatism and CMS reimbursement confusion continue to limit widespread use of the therapy.

Roger Macklis, M.D. Cleveland Clinic

Steven Larson, M.D. Memorial Sloan-Kettering Cancer Center

Betsy de Parry Ann Arbor, Mich.

About 60,000 Americans are diagnosed with NHL and 20,000 die from it each year. Fewer than 2,000 annually receive radioimmunotherapy.

The first FDA-approved RIT agent was yttrium 90-ibritumomab tiuxetan (Zevalin®), originally developed by Biogen Idec and now licensed to Cell Therapeutics. Subsequently approved iodine 131-tositumomab (Bexxar®), came from the Corixa Corporation, which is now owned by GlaxoSmithKline. These agents marshal radiolabeled antibodies that seek and bind to CD 20 receptors on B cell lymphoma, killing the malignant cells.

Some practitioners believe RIT agents may result in less durable outcomes than chemotherapy, unconjugated antibody or other treatments. However, supporters assert that, in addition to being useful for treating patients with recurrent disease, RIT agents have enormous promise if approved for upfront treatment, when they can best shut down the disease in patients who may be more responsive to therapy.

FDA approval currently restricts usage to more seriously compromised patients with relapsed or refractory follicular B-cell NHL, for whom extensive chemotherapy and non-radioactive antibody treatments have already failed.

The new therapy is "quite well tolerated, compared to most chemotherapy," said Susan Knox, M.D., Ph.D., an associate professor of radiation oncology at Stanford University in California, which treats many patients annually. "Among patients considered incurable, we have had relatively high and durable response rates."

Lymphoma Survivor is Advocate

Betsy de Parry, of Ann Arbor, Mich., was an early recipient of Zevalin, approved by FDA in 2002, the same year de Parry was diagnosed with Stage IV NHL at age 52. The marketing executive underwent cyclophosphamide, vincristine and prednisone (CVP) and cyclophosphamide, doxorubicin, vincristine and prednisolone plus rituximab (R-CHOP) chemotherapy but the disease was refractory to both.

"Chemotherapy just wasn't working for me and my options were fairly limited," said de Parry. The cost of treatment and side effects to that point was $162,410. In September 2002, she received Zevalin, a onetime regimen costing $36,930. Five and a half years later, "I'm alive," she said. "I've never had a recurrence, never been retreated. There's no evidence of disease in my body."

Though not all people with NHL are found suitable for RIT, researchers report response rates of up to 95 percent, tumor regression within 2 weeks and 5-year progression-free survival rates of 77 percent for Bexxar patients with a complete response. Physicians and pharmaceutical company representatives said they are disappointed that what seemed like a surefire, life-extending treatment has been used so sparingly.

Marketing of RIT agents, said Dr. Knox, originally focused on medical oncologists as gatekeepers, rather than radiation oncologists and nuclear medicine physicians. "As a field, we became involved later in the process and that was unfortunate," she said.

"There's an absolute need to have very, very strong evidence before a conventional treatment like chemotherapy is set aside for a new treatment like radiolabeled antibodies," said Steven Larson, M.D., chief of the Nuclear Medicine Service at New York's Memorial Sloan-Kettering Cancer Center. Dr. Larson serves on the RSNA News Editorial Board. "An inherent conservatism and economics run in the same direction." Therefore, what he describes as a "very effective immunologic therapy and targeted radiotherapy all in one go," continues, but as a last resort.

To receive RIT, patients must seek a radiation oncologist or nuclear medicine physician and leave their medical oncologists, who have little incentive to refer them. Roger Macklis, M.D., a longtime radioimmunotherapy investigator and former chair of the Department of Radiation Oncology at the Cleveland Clinic, said Zevalin and Bexxar represent a clear therapeutic advance. "Though expected to go flying off the shelves, they didn't," he said. An entirely new multidisciplinary team and delivery system is needed, he said, and most medical oncologists, not licensed to administer it, haven't seen curative or even long-term complete remissions that merit the loss of income and control.

Data Expected to Drive Changes

Dr. Larson said he believes that once the data are clear, interspecialty coordination will ramp up because "most doctors would be extremely reluctant to treat their patients with something not absolutely the best." Clinicians are hopeful that Phase III, multicenter trials under way may further validate and free these radiolabeled antibodies for earlier, frontline treatment.

Oliver Press, M.D., Ph.D, a medical oncologist at the University of Washington in Seattle, is coordinating major Bexxar trials at 300-plus cancer centers involving nearly 550 patients. "These are frontline trials in newly diagnosed patients, who receive both chemotherapy and radiolabeled antibodies, so it's a new use," said Dr. Press, who also chairs the Lymphoma Research Foundation's Scientific Advisory Board. "It's already been pretty clearly demonstrated that RIT is helpful in patients with relapsed lymphoma. If there's a dramatic improvement on this trial, it may make a big difference in the utilization of Bexxar." While results may be 2 years away, recent European trials of Zevalin have suggested clear benefits to this combined modality approach.

An Italian study published in the April issue of The Lancet Oncology followed 57 patients deemed eligible for Zevalin treatment after chemotherapy. Following the participants for an average of 30 months, the researchers found that 3-year progression-free survival was 76 percent and 3-year overall survival was 100 percent.

A final roadblock to RIT appeared when CMS reduced reimbursement rates for 2008 to well below reported acquisition costs, leaving practitioners to decide whether to subsidize or abandon the drugs. Physicians, hospitals and others raised an outcry and persuaded Congress to intervene and fully reimburse through June 2008.

With minimal, restricted use, drug manufacturers were under financial pressure, jeopardizing the availability of the agents for Medicare, Medicaid and even privately insured patients.

De Parry accompanied Bexxar co-developer Mark Kaminski, M.D., of the University of Michigan, to meet with CMS Deputy Administrator Herb B. Kuhn in February.

Emphasizing the success of RIT, advocates argued against the CMS reimbursement formula, specifically objecting to flawed cost estimates and the splitting of dosimetric rounds out of a single therapeutic regimen. Kuhn has also heard from Congressional supporters who want full reimbursement until December and more realistic reimbursement rates for 2009.

In their CMS presentation, RIT advocates cited "encouraging data ... that has some scientists whispering the word 'cure."' While some researchers don't go that far, they still express excitement for the future of the treatment. There are many new antibodies being developed and new ways of improving their use, said Dr. Macklis. "This is the most exciting era to be a lymphoma researcher," he said. "We need to understand how to sequence the various therapeutic strategies and team up the specialists for the general welfare of patients."