Late Effects May Not Warrant Adding Radiation to Chemotherapy for Early-Stage Hodgkin Lymphoma >> NCI Cancer Bulletin for December 13, 2011 - National Cancer Institute

Late Effects May Not Warrant Adding Radiation to Chemotherapy for Early-Stage Hodgkin Lymphoma

Hodgkin lymphoma is a cancer of the immune system marked by the presence of large cells called the Reed-Sternberg cell. The number of these cells increases as the disease advances. Photo by Wellcome Images

Patients with early-stage Hodgkin lymphoma who were treated with multidrug chemotherapy alone were more likely to be alive 12 years later than patients who received the same chemotherapy plus radiation therapy, according to findings from a phase III clinical trial. More patients who received radiation therapy in addition to chemotherapy died of second cancers or other toxic late effects of their treatment, such as heart disease, than those who received chemotherapy alone, researchers reported Monday at the American Society of Hematology (ASH) annual scientific meeting in San Diego. The findings, which are the first long-term results from a randomized trial involving patients with early-stage Hodgkin lymphoma, also appeared online December 11 in the New England Journal of Medicine. 

The overall survival rate was 94 percent for patients treated with the drugs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD regimen), compared with 87 percent for patients who received either radiation therapy alone or ABVD plus radiation therapy. Of 405 patients enrolled in the trial, 12 in the ABVD-alone group died during the follow-up period (six of Hodgkin lymphoma, four of second cancers, and two of other causes). In contrast, 24 patients in the group receiving radiation therapy died (4 of Hodgkin lymphoma, 10 of second cancers, and 10 of other causes).

All of the trial's participants had stage IA or IIA Hodgkin lymphoma, with tumors smaller than 4 inches in diameter. Hodgkin lymphoma occurs most often in younger people, and the median age of the participants in the trial was about 36 when the study began. Among the roughly two-thirds of participants with high-risk disease, 92 percent of those treated with ABVD alone were alive at 12 years, compared with 81 percent of those who received radiation therapy.

The rate of freedom from disease progression was lower in the group of patients treated with chemotherapy alone (87 percent) than in the group receiving radiation (92 percent), principal investigator Dr. Ralph M. Meyer, of the National Cancer Institute of Canada (NCIC) Clinical Trials Group, acknowledged at a press briefing on Sunday.

"What we have shown is that ... chemotherapy [alone] improves overall survival, and it does so because there are fewer late effects than with a treatment strategy that includes radiation," Dr. Meyer said. "We have also shown that the standard paradigm of keeping the disease away being a proxy measure for living longer doesn't apply in this situation because of the late effects."

Most trials involving patients with stage IA or IIA Hodgkin lymphoma have followed the participants for 4 to 6 years and have used disease recurrence as the primary outcome measure, Dr. Meyer noted. However, late effects associated with radiation therapy do not become apparent for 10 years or more, he continued.
"The treatment of Hodgkin lymphoma today is a real balance between achieving control of the disease and cure while limiting long-term side effects," commented Dr. Jane N. Winter, who moderated the press briefing and is a past co-chair of the lymphoma committee of the Eastern Cooperative Oncology Group, which participated in the study. "This [study speaks] to that balance and [to] the importance of long-term follow-up in evaluating our new therapies."

The type of radiation therapy used in the study, known as subtotal nodal radiation therapy, is now considered outdated, added Dr. Meyer. "The treatment that the patients in the control arm received would today be considered excessive and likely contributed to the additional second cancers and cardiovascular events," he said. Although the risks of late effects associated with radiation therapy "are likely reduced with modern strategies, we don't know the magnitude by which they are reduced," he continued.

The NCIC trial results "confirm the known long-term detrimental effects of large-field radiation therapy, an approach that has long been abandoned given the large body of literature on the late effects of such treatment, and the similar efficacy of more limited radiation treatment fields as part of combined modality therapy," Drs. Peter Mauch and Andrea Ng, radiation oncologists at Harvard Medical School, wrote in an e-mail. Today, radiation doses are a fraction of those used in this trial, and treatment is limited to the area of the body affected by lymphoma, they explained.

"Clinical trials have shown that higher rates of recurrence are associated with increased mortality from Hodgkin lymphoma," Drs. Mauch and Ng continued. "The challenge is how to minimize recurrence while limiting the late mortality associated with treatment. Much has been achieved towards this goal with the use of reduced number of courses of chemotherapy and limiting the dose and field size of radiation."

Radiation oncologists have been divided over the role of radiation therapy in patients with stage IA or IIA Hodgkin lymphoma, said Dr. Richard Little of NCI's Cancer Therapy Evaluation Program. "Data from this study, which is the first published randomized trial with longer-term follow-up, will be taken by many to mean [that] omission of radiation therapy should be the standard of care in early-stage Hodgkin lymphoma," he said. "However, some patients and physicians will be so averse to the slight increase in early disease progression if radiotherapy is omitted that it will not be omitted in all cases."
—Eleanor Mayfield
NCI Cancer Bulletin for December 13, 2011 - National Cancer Institute