Long-Term Data Support Chemo Alone in Hodgkin's Lymphoma

Zosia Chustecka

December 11, 2011

December 11, 2011 (San Diego, California) — New long-term data have shifted the debate over the best treatment for patients with limited-stage Hodgkin's disease in favor of chemotherapy alone, and have highlighted the risk for late complications from radiotherapy.

The new long-term data, from a 12-year follow-up of the Hodgkin's Disease 6 trial (HD6), were presented here at the American Society of Hematology (ASH) 53rd Annual Meeting and published simultaneously online December 11 in the New England Journal of Medicine.

Chemotherapy alone was associated with a higher overall survival when compared with radiation with or without chemotherapy (94% vs 87% of patients were still alive at 12 years; hazard ratio, 0.50; 95% confidence interval, 0.25 - 0.99; P = .04). The main reason was fewer deaths from causes other than Hodgkin's lymphoma, including secondary cancers and cardiovascular events, said lead investigator Ralph Meyer, MD, from Queen's University, Kingston, Ontario, Canada.

Commenting on the study for Medscape Medical News, ASH President J. Evan Sadler, MD, PhD, professor of medicine in the Division of Hematology at Washington University in St. Louis, Missouri, said: "I interpret this study as evidence that the long-term complications of radiotherapy are not necessarily worth the short-term efficacy".

In the shorter term, the results from radiotherapy in combination with chemotherapy do look better, he said. "Now, looking at the very long-term data, the morbidity and mortality associated with late complications from radiotherapy may well trump this short-term effectiveness," he added.

Long-term survival is the most important treatment outcome, and "this is the first trial that used late survival as the primary end point," noted David Strauss, MD from the lymphoma service at the Memorial Sloan-Kettering Cancer Center, New York City, in an editorial accompanying the New England Journal of Medicine article.

Patients treated with radiation developed more secondary cancers and cardiovascular events, he noted, adding that deaths from these causes increase dramatically after 10 years, and so it could be expected that the rate of survival in these patients may decrease even further in the future.

Long Wait for Results

The HD6 trialists have been very patient, waiting for 17 years for assessment of the primary end-point, and "the results have been well worth the wait," the editorialist comments.

When the study began in 1994, the standard of care for these patients with early-stage Hodgkin's lymphoma was radiotherapy, which in the trial was delivered as extended field subtotal nodal radiation (up to 35 Gy in 20 daily fractions). "This is no longer practiced today," Dr. Meyer commented at a press briefing, "and it would now be considered excessive."

How the results from this radiotherapy compare with modern radiotherapy approaches used now is one of the "core issues" with these data, and is discussed at length in both the published paper and the editorial, he noted.

The experimental group in the trial was chemotherapy alone, in which patients were given up to 4 or 6 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Patients assigned to radiotherapy who had an unfavorable risk profile (139/203 patients) also received chemotherapy, given as 2 cycles of ABVD.

At 12 years' follow-up, there were significantly fewer deaths in the group treated with chemotherapy alone compared with those treated with radiotherapy (12 vs 24).

The difference was primarily a result of death from causes other than Hodgkin's lymphoma, Dr. Meyers noted. There were 6 deaths from Hodgkin's lymphoma or an early-treatment complication of treatment in the chemotherapy-alone group, and 4 such deaths in the radiotherapy group, but there were only 6 deaths from other causes (4 from secondary cancers and 2 from cardiac events) in the chemotherapy-alone group compared with 20 such deaths in the radiotherapy groups (of which 10 were caused by secondary cancers and 2 by cardiac events).

When considering all patients, and not just those who died, secondary cancers were more common among those treated with radiotherapy (23 patients vs 10 receiving chemotherapy alone), as were cardiac events (26 vs 16).

Better Disease Control

Patients treated with radiotherapy showed a benefit over those treated with chemotherapy alone in one aspect: they had better disease control. The rate of freedom from disease progression was significantly lower (12-year estimates, 87% vs 92%; hazard ratio for disease progression, 1.91; 95% confidence interval, 0.99 - 3.69; P = .05) among patients who had received radiotherapy.

However, these results challenge the notion that "keeping the disease away will keep patients living for longer," commented Dr. Myers, and these 12-year data show that this is not the case. Hodgkin's lymphoma is a "highly curable disease," and the mean age of patients is around 35 years. Thus, these new data "emphasize the importance of frontline treatment that is provided," he commented.

"The results of our study suggest that in the long term, patients with limited-stage Hodgkin's lymphoma may be better served by a treatment approach that uses chemotherapy without radiation, as this method seems to be associated with fewer deaths from other causes," Dr. Meyer concluded.

Debate Continues, but Practice Will Shift

The debate over whether to use radiation as well as chemotherapy has raged fiercely for some years now, as previously reported by Medscape Medical News.

At present there is a split worldwide in how clinicians treat these patients, Dr. Meyers commented at the press briefing, with some using radiotherapy and others not. Although the old-fashioned radiotherapy used in this trial will fuel further debate over how these results apply to modern radiotherapy, and whether the long-term complications would be similar, Dr. Myers predicted that these new results will have an effect on clinical practice. He predicted that the proportion of physicians opting for each of the 2 approaches will change, and that clinicians more will now opt to use chemotherapy alone.

ASH Secretary Charles Abrams, MD, who was coordinator of the abstracts review and is associate chief of the Division of Hematology/Oncology at the University of Pennsylvania in Philadelphia, commented that this was a very well-designed study with very long-term follow-up. In answer to the question of whether this is a final answer, he said: "I doubt that there will be another trial like this."

The HD-6 trial was supported by a grant from the Canadian Cancer Society Research Institute. Dr. Myers reports receiving honoraria from Lilly and Cologne, and other coauthors also report relationships with industry, as detailed in the article.

American Society of Hematology (ASH) 53rd Annual Meeting: Abstract 590. Presented December 12, 2011.

N Eng J Med. Published online December 11, 2011. Full text, Editorial


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